Inhibitors of the HIV integrase enzyme

ABSTRACT

The present invention is directed to compounds of formula (i),  
                 
and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the human immunodeficiency virus (“HIV”) integrase enzyme.

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application Nos. 60/565,728, filed Apr. 26, 2004,60/643,316, filed Jan. 11, 2005, 60/657,594, filed Feb. 28, 2005, and60/660,430, filed Mar. 9, 2005, all of which are hereby incorporated byreference.

FIELD

The present invention is directed to compounds, and pharmaceuticallyacceptable salts and solvates thereof, their synthesis, and their use asmodulators or inhibitors of the human immunodeficiency virus (“HIV”)integrase enzyme. The compounds of the present invention are useful formodulating (e.g. inhibiting) an enzyme activity of HIV integrase enzymeand for treating diseases or conditions mediated by HIV, such as forexample, acquired immunodeficiency syndrome (“AIDS”), and AIDS relatedcomplex (“ARC”).

BACKGROUND

The retrovirus designated “human immunodeficiency virus” or “HIV” is theetiological agent of a complex disease that progressively destroys theimmune system. The disease is known as acquired immune deficiencysyndrome or AIDS. AIDS and other HIV-caused diseases are difficult totreat due to the ability of HIV to rapidly replicate, mutate and acquireresistance to drugs. In order to slow the proliferation of the virusafter infection, treatment of AIDS and other HIV-caused diseases hasfocused on inhibiting HIV replication.

Since HIV is a retrovirus, and thus, encodes a positive-sense RNAstrand, its mechanism of replication is based on the conversion of viralRNA to viral DNA, and subsequent insertion of the viral DNA into thehost cell genome. HIV replication relies on three constitutive HIVencoded enzymes: reverse transcriptase (RT), protease and integrase.

Upon infection with HIV, the retroviral core particles bind to specificcellular receptors and gain entry into the host cell cytoplasm. Onceinside the cytoplasm, viral RT catalyzes the reverse transcription ofviral ssRNA to form viral RNA-DNA hybrids. The RNA strand from thehybrid is then partially degraded and a second DNA strand is synthesizedresulting in viral dsDNA. Integrase, aided by viral and cellularproteins, then transports the viral dsDNA into the host cell nucleus asa component of the pre-integration complex (PIC). In addition, integraseprovides the permanent insertion, i.e., integration, of the viral dsDNAto the host cell genome, which, in turn, provides viral access to thehost cellular machinery for gene expression. Following integration,transcription and translation produce viral precursor proteins.

A key step in HIV replication, insertion of the viral dsDNA into thehost cell genome, is believed to be mediated by integrase in at leastthree, and possibly, four, steps: (1) assembly of proviral DNA; (2)3′-end processing causing assembly of the PIC; (3) 3′-end joining or DNAstrand transfer, i.e., integration; and (4) gap filling, a repairfunction. See, e.g., Goldgur, Y. et al., PNAS 96(23): 13040-13043 (Nov.1999); Sayasith, K. et al., Expert Opin. Ther. Targets 5(4): 443-464(2001); Young, S. D., Curr. Opin. Drug Disc. & Devel. 4(4): 402-410(2001); Wai, J. S. et al., J. Med. Chem. 43(26): 4923-4926 (2000);Debyser, Z. et al., Assays for the Evaluation of HIV-1 IntegraseInhibitors, from Methods in Molecular Biology 160: 139-155, Schein, C.H. (ed.), Humana Press Inc., Totowa, N.J. (2001); and Hazuda, D. et al.,Drug Design and Disc. 13:17-24 (1997).

Currently, AIDS and other HIV-caused disease are treated with an “HIVcocktail” containing multiple drugs including RT and proteaseinhibitors. However, numerous side effects and the rapid emergence ofdrug resistance limit the ability of the RT and protease inhibitors tosafely and effectively treat AIDS and other HIV-caused diseases. In viewof the shortcomings of RT and protease inhibitors, there is a need foranother mechanism through which HIV replication can be inhibited.Integration, and thus integrase, a virally encoded enzyme with nomammalian counterpart, is a logical alternative. See, e.g., Wai, J. S.et al., J. Med. Chem. 43:4923-4926 (2000); Grobler, J. et al., PNAS 99:6661-6666 (2002); Pais, G. C:G. et al., J. Med. Chem. 45: 3184-3194(2002); Young, S. D., Curr. Opin. Drug Disc. & Devel. 4(4): 402-410(2001); Godwin, C. G. et al., J. Med. Chem. 45: 3184-3194 (2002); Young,S. D. et al., “L-870, 810: Discovery of a Potent HIV Integrase Inhibitorwith Potential Clinical Utility,” Poster presented at the XIVInternational AIDS Conference, Barcelona (July 7-12, 2002); and WO02/070491.

It has been suggested that for an integrase inhibitor to function, itshould inhibit the strand transfer integrase function. See, e.g., Young,S. D., Curr. Opin. Drug Disc. & Devel. 4(4): 402-410 (2001). Thus, thereis a need for HIV inhibitors, specifically, integrase inhibitors, and,more specifically, strand transfer inhibitors, to treat AIDS and otherHIV-caused diseases. The inventive agents disclosed herein are novel,potent and selective HIV-integrase inhibitors, and, more specifically,strand transfer inhibitors, with high antiviral activity.

SUMMARY

The present invention provides compounds of formula (I),

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl,wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups maybe optionally substituted with at least one substituent independentlyselected from:

-   -   halo, —OR^(12a), —N(R^(12a)R^(12b), —C(O)N(R^(12a)R^(12b))        —NR^(12a)C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)R^(12a),        —NR^(12a)C(NR^(12a))N(R^(12a)R^(12b)), —SR^(12a), —S(O)R^(12a),        —S(O)₂R^(12a), —S(O)₂N(R^(12a)R^(12b)), C₁-C₈ alkyl, C₆-C₁₄        aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈        alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl        groups are optionally substituted with at least one substituent        independently selected from halo, —C(R^(12a)R^(12b)R^(12c)),        —OH, and C₁-C₈ alkoxy;

R² is hydrogen or C₁-C₈ alkyl;

R³ is hydrogen, C₁-C₈ alkyl, —(CR⁷R⁸)_(t)NR⁹R¹⁰, —S(O)_(z)NR⁹R¹⁰,—C(O)NR⁹R¹⁰, or C₁-C₈ heteroalkyl, wherein said C₁-C₈ heteroalkyl isoptionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group; or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a),—CO₂R^(12a), and —OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen, C₁-C₈ alkyl, and oxo; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷,—(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3;

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; and

each z, which may be the same or different, is independently selectedand is 0, 1, or 2; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

Also provided herein are compounds of formula (I) wherein Z is—C(R⁴)═C(R⁴)—, or —C(H)═C(H)—.

Also provided herein are compounds of formula (i), wherein R¹³ isindependently selected from C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a),—S(O)₂R⁷, —(CR⁷R⁸)₂C(O)NR^(12a)R^(12b), and —NR^(12a)R^(12b).

Further provided herein are compounds of formula (I), wherein R¹³ isindependently selected from C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a),—S(O)₂R⁷, —C(O)NR^(12a)R^(12b), and —NR^(12a)R^(12b).

Also provided herein are compounds of formula (I), wherein R¹³ isselected from C₁-C₈ alkyl and —C(O)NR^(12a)R^(12b).

Further provided herein are compounds of formula (I), wherein R¹³ isselected from C₁-C₈ alkyl and —C(O)NH₂.

The present invention also provides compounds of formula (I),

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl,wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups maybe optionally substituted with at least one substituent independentlyselected from:

-   -   halo, —OR^(12a), —N(R^(12a)R^(12b)), C(O)N(R^(12a)R^(12b)),        —NR^(12a)C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)R^(12a),        —NR^(12a)C(NR^(12a))N(R^(12a)R^(12b)), —SR^(12a), —S(O)R^(12a),        —S(O)₂R^(12a), —S(O)₂N(R^(12a)R^(12b)), C₁-C₈ alkyl, C₆-C₁₄        aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈        alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl        groups are optionally substituted with at least one substituent        independently selected from halo, —C(R^(12a)R^(12b)R^(12c)),        —OH, and C₁-C₈ alkoxy;

R² is hydrogen or C₁-C₈ alkyl;

R³ is hydrogen, —(CR⁷R⁸)_(t)NR⁹R¹⁰ or C₁-C₈ heteroalkyl, wherein saidC₁-C₈ heteroalkyl is optionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl group optionally substituted with at leastone C₁-C₈ alkyl;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a),—CO₂R^(12a), and —OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

In another aspect of the present invention are afforded compounds offormula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-Cl₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one substituentindependently selected from halo, —C(R^(12a)R^(12b)R^(12c)), —OH, andC₁-C₈ alkoxy;

R² is hydrogen;

R³ is hydrogen, —(CR⁷R⁸)_(t)NR⁹R¹⁰ or C₁-C₈ heteroalkyl, wherein saidC₁-C₈ heteroalkyl is optionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—, —(CR⁴R⁴)_(n)—C(R⁴)′C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, where C₁-C₈ alkyl is optionally substituted with at least oneC₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl group optionally substituted with at leastone C₁-C₈ alkyl;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a), and—OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)—OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

In still a further aspect of the present invention are providedcompounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one halo;

R² is hydrogen;

R³ is hydrogen, —(CR⁷R⁸)_(t)NR⁹R¹⁰ or C₁-C₈ heteroalkyl, wherein saidC₁-C₈ heteroalkyl is optionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl group optionally substituted with at leastone C₁-C₈ alkyl;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a),—CO₂R^(12a), and —OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or pharmaceutically acceptable salts orsolvates thereof, with the proviso that R⁵ is not hydrogen when Z is—(CH₂)—, R¹ is 2,4-difluorobenzyl, and R², R³, and R⁶ are hydrogen.

The present invention also affords compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one halo;

R² is hydrogen;

R³ is hydrogen;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴) _(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C_(1-C) ₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

Yet another aspect of the present invention are compounds of formula(I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one fluorine;

R² is hydrogen;

R³is hydrogen;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n—, —(CR)⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C_(1-C) ₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or P pharmaceutically acceptable salts orsolvates thereof, with the proviso that R⁵ is not hydrogen when Z is—(CH₂)—, R¹ is 2,4-difluorobenzyl, and R², R³, and R⁶ are hydrogen.

A still further aspect are compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one halo;

R² is hydrogen;

R³is —(CR⁷R⁸)_(t)NR⁹R¹⁰;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl group optionally substituted with at leastone C₁-C₈ alkyl;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

Also provided are compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one fluorine;

R² is hydrogen;

R³ is —(CR⁷R⁸)_(t)NR⁹R¹⁰;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴) _(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₃heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl group optionally substituted with at leastone C₁-C₈ alkyl;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or pharmaceutically acceptable salts orsolvates thereof, with the proviso that R⁵ is not hydrogen when Z is—(CH₂)—, R¹ is 2,4-difluorobenzyl, and R², R³, and R⁶ are hydrogen.

Also provided are compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one halo;

R² is hydrogen;

R³ is C₁-C₈ heteroalkyl optionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶ is hydrogen;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a),—CO₂R^(12a), and —OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁵ are hydrogen.

Furthermore, compounds of formula (I) are provided, wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one fluorine;

R² is hydrogen;

R³ is C₁-C₈ heteroalkyl optionally substituted with R¹¹;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR ⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, where C₁-C₈ alkyl is optionally substituted with at least oneC₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

R⁶is hydrogen;

R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl,C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionallysubstituted with at least one substituent independently selected fromC₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a),—CO₂R^(12a), and —OR^(12a);

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃;

t is an integer from 1 to 3; and

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; or

pharmaceutically acceptable salts or solvates thereof, with the provisothat R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, andR², R³, and R⁶ are hydrogen.

In a still further aspect of the present invention are providedcompounds of formula (i), wherein:

R is —(CR⁷R⁸)_(t)NR⁹R¹⁰; and

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group;

Further provided are compounds of formula (I), wherein:

R³ is —(CR⁷R⁸)_(t)NR⁹R¹⁰;

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group.

In yet a further aspect are afforded compounds of formula (II),

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl,wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups maybe optionally substituted with at least one substituent independentlyselected from:

-   -   halo, —OR^(12a), —N(R^(12a)R^(12b)), —C(O)N(R^(12a)R^(12b)),        —NR^(12a)C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)R^(12a),        —NR^(12a)C(NR^(12a))N(R^(12a)R^(12b)), —SR^(12a), S(O)R^(12a),        S(O)₂R^(12a), —S(O)₂N(R^(12a)R^(12b)), C₁-C₈ alkyl, C₆-C₁₄ aryl,        C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈        alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl        groups are optionally substituted with at least one substituent        independently selected from halo, —C(R^(12a)R^(12b)R^(12c)),        —OH, and C₁-C₈ alkoxy;

X is —S(O)₂—, —CH₂—, or —C(O)—;

Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—,—(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—;

each R⁴ is independently selected from hydrogen, halo, C₁-C₈heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroarylare optionally substituted with at least one R¹³;

R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at leastone C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group; or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen, C₁-C₈ alkyl, and oxo; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group;

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷, —(CR⁷R⁸)₂C(O)N^(12a)R^(12b),—NR^(12a)R^(12b), and —CF₃;

each n, which may be the same or different, is independently selectedand is an integer from 1 to 4; and

each z, which may be the same or different, is independently selectedand is 0, 1, or 2; or

pharmaceutically acceptable salts or solvates thereof.

In still another aspect are provided compounds of formula (III),

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl,wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups maybe optionally substituted with at least one substituent independentlyselected from:

-   -   halo, —OR^(12a), —N(R^(12a)R^(12b)), C(O)N(R^(12a)R^(12b)),        —NR^(12a)C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)R^(12a),        —NR^(12a)C(NR^(12a))N(R^(12a)R^(12b)), —SR^(12a), —S(O)R^(12a),        —S(O)₂R^(12a), —S(O)₂N(R^(12a)R^(12b)), C₁-C₈ alkyl, C₆-C₁₄        aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈        alkyl, C₆-C₁₄ aryl, C3-C₈ cycloalkyl, and C₂-C₉ heteroaryl        groups are optionally substituted with at least one substituent        independently selected from halo, —C(R^(12a)R^(12b)R^(12c)),        —OH, and C₁-C₈ alkoxy;

X is —S(O)₂—, —CH₂—, or —C(O)—;

each R⁷ and R⁸, which may be the same or different, are independentlyselected from hydrogen and C₁-C₈ alkyl;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may

be optionally substituted by at least one C₂-C₉ cycloheteroalkyl, C₂-C₉heteroaryl, halo, or C₆-C₁₄ aryl group, and wherein said C₆-C₁₄ arylgroup may be optionally substituted by at least one C₁-C₈ or halo group;or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen, C₁-C₈ alkyl, and oxo; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group;

each R¹³ is independently selected from halo, C₁-C₈ alkyl, —(CR⁷R)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷, —(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b),—NR^(12a)R^(12b), and —CF₃; and

each z, which may be the same or different, is independently selectedand is 0, 1, or 2; or

pharmaceutically acceptable salts or solvates thereof.

Further provided herein are compounds of formula (IIIa):

wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one substituentindependently selected from halo, —C(R^(12a)R^(12b)R^(12c)), —OH, andC₁-C₈ alkoxy;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group; or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group; and

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷,—(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), —NR^(12a)R^(12b), and —CF₃; or

pharmaceutically acceptable salts or solvates thereof.

Further provided are compounds of formula (IIIa), wherein R⁹ and R¹⁰,which may be the same or different, are independently selected fromhydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, and C₁-C₈ alkyl,wherein said C₁-C₈ alkyl may be optionally substituted by at least oneC₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄ aryl group,and wherein said C₆-C₁₄ aryl group may be optionally substituted by atleast one C₁-C₈ or halo group.

Also provided are compounds of formula (IIIa), wherein R⁹ and R¹⁰,together with the nitrogen atom to which they are attached, form a C₂-C₉cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which isoptionally substituted with at least one R¹³ group.

Further provided herein are compounds of formula (IIIb),

wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one substituentindependently selected from halo, —C(R ^(12a)R^(12b)R^(12c)), —OH, andC₁-C₈ alkoxy;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group; or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group; and

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷,—(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), —NR^(12a)R^(12b), and —CF₃; or

pharmaceutically acceptable salts or solvates thereof.

Further provided are compounds of formula (IIIb), wherein R⁹ and R¹⁰,which may be the same or different, are independently selected fromhydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, and C₁-C₈ alkyl,wherein said C₁-C₈ alkyl may be optionally substituted by at least oneC₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄ aryl group,and wherein said C₆-C₁₄ aryl group may be optionally substituted by atleast one C₁-C₈ or halo group.

Also provided are compounds of formula (IIIb), wherein R⁹ and R¹⁰,together with the nitrogen atom to which they are attached, form a C₂-C₉cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which isoptionally substituted with at least one R¹³ group.

In yet another aspect are provided compounds of formula (IIIc),

wherein:

R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ arylgroup is optionally substituted with at least one substituentindependently selected from halo, —C(R^(12a)R^(12b)R^(12c)), —OH, andC₁-C₈ alkoxy;

R⁹ and R¹⁰, which may be the same or different, are independentlyselected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, andC₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted byat least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄aryl group, and wherein said C₆-C₁₄ aryl group may be optionallysubstituted by at least one C₁-C₈ or halo group; or

R⁹ and R¹⁰, together with the nitrogen atom to which they are attached,form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of whichis optionally substituted with at least one R¹³ group;

each R^(12a), R^(12b), and R^(12c), which may be the same or different,is independently selected from hydrogen and C₁-C₈ alkyl; or

R^(12a) and R^(12b), together with the nitrogen atom to which they areattached, may form a C₂-C₉ cycloheteroalkyl group; and

each R¹³ is independently selected from halo, C₁-C₈ alkyl,—(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷,—(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), —NR^(12a)R^(12b), and —CF₃; or

pharmaceutically acceptable salts or solvates thereof.

Further provided are compounds of formula (IIIc), wherein R⁹ and R¹⁰,which may be the same or different, are independently selected fromhydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, and C₁-C₈ alkyl,wherein said C₁-C₈ alkyl may be optionally substituted by at least oneC₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄ aryl group,and wherein said C₆-C₁₄ aryl group may be optionally substituted by atleast one C₁-C₈ or halo group.

Also provided are compounds of formula (IIIc), wherein R⁹ and R¹⁰,together with the nitrogen atom to which they are attached, form a C₂-C₉cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which isoptionally substituted with at least one R¹³ group.

In yet another aspect are afforded any of the above compounds wherein Zis —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, or —(CH═CH)—.

Further provided are any of the above compounds wherein R⁹ and R¹⁰,together with the nitrogen atom to which they are attached, form a C₂-C₉cycloheteroalkyl group comprising 4 carbon atoms and a nitrogen atom; orwherein R9 and R¹⁰, together with the nitrogen atom to which they areattached, form a C₂-C₉ cycloheteroalkyl group comprising 4 carbon atomsand 2 nitrogen atoms; or wherein R⁹ and R¹⁰, together with the nitrogenatom to which they are attached, form a C₂-C₉ cycloheteroalkyl groupcomprising 4 carbon atoms, a nitrogen atom, and an oxygen atom, providedthat said nitrogen atom and said oxygen atom are not bonded to eachother; or wherein R⁹ and R¹⁰, together with the nitrogen atom to whichthey are attached, form a C₂-C₉ cycloheteroalkyl group comprising 4carbon atoms, a nitrogen atom, and a sulfur atom; or wherein R⁹ and R¹⁰,together with the nitrogen atom to which they are attached, form a C₂-C₉cycloheteroalkyl group comprising 4 carbon atoms, a nitrogen atom, andan oxidized sulfur atom; or wherein R⁹ and R¹⁰, together with thenitrogen atom to which they are attached, form a C₂-C₉ cycloheteroalkylgroup comprising three carbon atoms and three nitrogen atoms.

Also provided are compounds selected from3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one;1-[(dimethylamino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-L-prolinamide;3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(4-methylpiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-(3,4-dihydroisoquinolin-2(1H)-ylmethyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(pentyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-D-prolinamide;3-(4-fluorobenzyl)-7-hydroxy-1-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[cyclohexyl(ethyl)amino]methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(2-pyridin-2-ylethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;(3R)-1-{([3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-N,N-dimethylpyrrolidine-3-carboxamide;3-(4-fluorobenzyl)-7-hydroxy-1-({4-hydroxy-4-[(2-oxopyrrolidin-1-yl)methyl]piperidin-1-yl}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(5-oxo-1,4-diazepan-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]sulfonyl}-L-prolinamide;3-(4-fluorobenzyl)-7-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide;3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)sulfonyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-N,N-dimethyl-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide;3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide;N,3-bis(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide;3-(4-fluorobenzyl)-7-hydroxy-1-(pyrrolidin-1-ylcarbonyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-[(4-acetylpiperazin-1-yl)carbonyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2-pyrazin-2-ylethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide;3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(pyridin-2-ylmethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide;3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide;1-[(4-ethylpiperazin-1-yl)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-({[(2S)-2,3-dihydroxypropyl]oxy}methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;tert-butyl4-({[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methoxy}methyl)piperidine-1-carboxylate;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-pyridin-2-ylethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[2-(cyclohexyloxy)ethoxy]methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-[({([(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(tetrahydro-2H-pyran-4-yloxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(1R)-1-phenylethoxy]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(propylamino)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(3-methylbenzyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-({[(5-methylpiperazin-2-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-({[4-(trifluoromethyl)benzyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(pyridin-2-ylmethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one;8-butyl-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-8-methyl-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one,3-(4-fluorobenzyl)-7-hydroxy-1-{[(2-hydroxyethyl)(propyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[2-(hydroxymethyl)piperidin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[[2-(diethylamino)ethyl](ethyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[ethyl(4-methylbenzyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[4-(ethylsulfonyl)piperazin-1-yl]methyl-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(4-hydroxypiperidin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[benzyl(methyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(7R)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(3aR,7aR)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-(morpholin-4-ylmethyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[4-(2-morpholin-4-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;and3-(4-fluorobenzyl)-7-hydroxy-1-({methyl[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;or pharmaceutically acceptable salts or solvates thereof.

In a further aspect are provided compounds selected from3-(4-Fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-Fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-(3,4-dihydroisoquinolin-2(1H)-ylmethyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-[({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(1R)-1-phenylethoxy]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-({[4-(trifluoromethyl)benzyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(pyridin-2-ylmethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;or pharmaceutically acceptable salts or solvates thereof.

Further provided are compounds selected from1-[(dimethylamino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(4-methylpiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(pentyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-D-prolinamide;1-{[cyclohexyl(ethyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-1-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(2-pyridin-2-ylethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-N,N-dimethyl-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide;3-(4-fluorobenzyl)-7-hydroxy-1-(pyrrolidin-1-ylcarbonyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;tert-butyl4-({[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methoxy}methyl)piperidine-1-carboxylate;3-(4-fluorobenzyl)-7-hydroxy-1-[(2-pyridin-2-ylethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;1-{[2-(cyclohexyloxy)ethoxy]methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(tetrahydro-2H-pyran-4-yloxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-({[1-(hydroxymethyl)cyclopentyl]amino7methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-[(propylamino)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;3-(4-fluorobenzyl)-7-hydroxy-1-{[(3-methylbenzyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;and3-(4-fluorobenzyl)-7-hydroxy-1-({[(5-methylpyrazin-2-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one;or pharmaceutically acceptable salts or solvates thereof.

The present invention also provides pharmaceutical compositions,comprising a therapeutically effective amount of at least one of any ofthe compounds herein, or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or diluent.

Further provided are methods of inhibiting HIV replication in a mammal,comprising administering to said mammal an HIV replication-inhibitingamount of at least one of any of the compounds herein, or apharmaceutically acceptable salt or solvate thereof.

In still another aspect of the present invention are afforded methods ofinhibiting HIV replication in a cell, comprising contacting said cellwith an HIV replication-inhibiting amount of at least one of any of thecompounds herein, or a pharmaceutically acceptable salt or solvatethereof.

Further provided herein are methods of inhibiting HIV integrase enzymeactivity, comprising contacting said integrase enzyme with an HIVintegrase-inhibiting amount of at least one of any of the compoundsherein, or a pharmaceutically acceptable salt or solvate thereof.

Additionally, the present invention affords methods of treating acquiredimmune deficiency syndrome in a mammal, such as a human, comprisingadministering to said mammal a therapeutically effective amount of atleast one of any of the compounds herein, or a pharmaceuticallyacceptable salt or solvate thereof.

The present invention further provides methods of inhibiting HIVreplication in a mammal, wherein said HIV is resistant to at least oneHIV protease inhibitor, said method comprising administering to saidmammal an HIV replication-inhibiting amount of at least one of any ofthe compounds herein, or a pharmaceutically acceptable salt or solvatethereof.

Also herein are methods of inhibiting HIV replication in a mammal,wherein said HIV is resistant to at least one HIV reverse transcriptaseinhibitor, said method comprising administering to said mammal an HIVreplication-inhibiting amount of at least one of any of the compoundsherein, or a pharmaceutically acceptable salt or solvate thereof.

In yet another aspect are provided methods of inhibiting HIV replicationin mammal, comprising administering to said mammal an HIVreplication-inhibiting amount of at least one of any of the compoundsherein, or a pharmaceutically acceptable salt or solvate thereof, and anHIV replication-inhibiting amount of at least one other anti-HIV agent.

In still another aspect are methods of reducing HIV viral load in amammal infected with HIV, such as a human, comprising administering tosaid mammal a therapeutically effective amount of at least one of any ofthe compounds herein, or a pharmaceutically acceptable salt or solvatethereof.

Further are provided uses of at least one of any of the compoundsherein, or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment of acquired immunedeficiency syndrome (AIDS) or AIDS-related complex in an HIV-infectedmammal.

Also provided herein are methods of treating HIV infection in anHIV-infected mammal, comprising administering to said mammal atherapeutically effective amount of at least one of any of the compoundsherein, or a pharmaceutically acceptable salt or solvate thereof.

It is to be understood that the compounds of the present invention donot include the compound of formula (I) wherein R¹ is2,4-difluorobenzyl, R² is hydrogen, R³ is hydrogen, Z is —(CH₂)—, and R⁶is hydrogen, which compound is named6-(2,4-difluorobenzyl)-2-hydroxy-1,6-dihydrodipyrrolo[3,2-d:3′,4′-b]pyridin-3(2H)-one.

As used herein, the terms “comprising” and “including” are used in theiropen, non-limiting sense.

As used herein, the term “HIV” means Human Immunodeficiency Virus. Theterm “HIV integrase,” as used herein, means the Human ImmunodeficiencyVirus integrase enzyme.

The term “C₁-C₈ alkyl”, as used herein, means saturated monovalenthydrocarbon radicals having straight or branched moieties and containingfrom 1 to 8 carbon atoms. Examples of such groups include, but are notlimited to, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, andtert-butyl.

The term “C₁-C₈ heteroalkyl” refers to a straight- or branched-chainalkyl group having a total of from 2 to 12 atoms in the chain, includingfrom 1 to 8 carbon atoms, and one or more atoms of which is a heteroatomselected from S, O, and N, with the proviso that said chain may notcontain two adjacent 0 atoms or two adjacent S atoms.—The S atoms insaid chains may be optionally oxidized with one or two oxygen atoms, toafford sulfides and sulfones, respectively. Furthermore, the C₁-C₈heteroalkyl groups in the compounds of the present invention can containan oxo group at any carbon or heteroatom that will result in a stablecompound. Exemplary C₁-C₈ heteroalkyl groups include, but are notlimited to, alcohols, alkyl ethers, primary, secondary, and tertiaryalkyl amines, amides, ketones, esters, sulfides, and sulfones.

The term “C₂-C₈ alkenyl”, as used herein, means an alkyl moietycomprising 2 to 8 carbons having at least one carbon-carbon double bond.The carbon-carbon double bond in such a group may be anywhere along the2 to 8 carbon chain that will result in a stable compound. Such groupsinclude both the E and Z isomers of said alkenyl moiety. Examples ofsuch groups include, but are not limited to, ethenyl, propenyl, butenyl,allyl, and pentenyl. The term “allyl,” as used herein, means a—CH₂CH═CH₂ group. The term, “C(R)═C(R),” as used herein, represents acarbon-carbon double bond in which each carbon is substituted by an Rgroup.

As used herein, the term “C₂-C₈ alkynyl” means an alkyl moietycomprising from 2 to 8 carbon atoms and having at least onecarbon-carbon triple bond. The carbon-carbon triple bond in such a groupmay be anywhere along the 2 to 8 carbon chain that will result in astable compound. Examples of such groups include, but are not limitedto, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne,2-hexyne, and 3-hexyne.

The term “C₃-C₈ cycloalkyl group” means a saturated, monocyclic, fused,spirocyclic, or polycyclic ring structure having a total of from 3 to 8carbon ring atoms. Examples of such groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cycloheptyl, and adamantyl.

The term “C₆-C₁₄ aryl”, as used herein, means a group derived from anaromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples ofsuch groups include, but are not limited to, phenyl or naphthyl. Theterms “Ph” and “phenyl,” as used herein, mean a —C₆H₅ group. The term“benzyl,” as used herein, means a —CH₂C₆H₅ group.

The term “C₂-C₉ heteroaryl, ” as used herein, means an aromaticheterocyclic group having a total of from 5 to 10 atoms in its ring, andcontaining from 2 to 9 carbon atoms and from one to four heteroatomseach independently selected from O, S and N, and with the proviso thatthe ring of said group does not contain two adjacent O atoms or twoadjacent S atoms. The heterocyclic groups include benzo-fused ringsystems. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The C₂-C₉ heteroaryl groups may be C-attached orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached).

The term “C₂-C₉ cycloheteroalkyl,” as used herein, means a non-aromatic,monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic grouphaving a total of from 4 to 10 atoms in its ring system, and containingfrom 2 to 9 carbon atoms and from one to four heteroatoms eachindependently selected from O, S and N, and with the proviso that thering of said group does not contain two adjacent O atoms or two adjacentS atoms. Furthermore, such C₂-C₉ cycloheteroalkyl groups may contain anoxo substituent at any available atom that will result in a stablecompound. For example, such a group may contain an oxo atom at anavailable carbon or nitrogen atom. Such a group may contain more thanone oxo substituent if chemically feasible. In addition, it is to beunderstood that when such a C₂-C₉ cycloheteroalkyl group contains asulfur atom, said sulfur atom may be oxidized with one or two oxygenatoms to afford either a sulfoxide or sulfone. An example of a 4membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5 membered heterocyclic group is thiazolyl and an exampleof a 10 membered heterocyclic group is quinolinyl. Further examples ofsuch C₂-C₉ cycloheteroalkyl groups include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl,4-ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl.

The term “C₁-C₈ alkoxy”, as used herein, means an 0-alkyl group whereinsaid alkyl group contains from 1 to 8 carbon atoms and is straight,branched, or cyclic. Examples of such groups include, but are notlimited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy,iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.

The terms “halogen” and “halo,” as used herein, mean fluorine, chlorine,bromine or iodine.

The term “substituted,” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted,” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. It is to be understood that in the compounds of thepresent invention when a group is said to be “unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all theatoms in the compound, the remaining valencies on such a group arefilled by hydrogen. For example, if a C₆ aryl group, also called“phenyl” herein, is substituted with one additional substituent, one ofordinary skill in the art would understand that such a group has 4 openpositions left on carbon atoms of the C₆ aryl ring (6 initial positions,minus one to which the remainder of the compound of the presentinvention is bonded, minus an additional substituent, to leave 4). Insuch cases, the remaining 4 carbon atoms are each bound to one hydrogenatom to fill their valencies. Similarly, if a C₆ aryl group in thepresent compounds is said to be “disubstituted,” one of ordinary skillin the art would understand it to mean that the C₆ aryl has 3 carbonatoms remaining that are unsubstituted. Those three unsubstituted carbonatoms are each bound to one hydrogen atom to fill their valencies.

The term “solvate,” as used herein, means a pharmaceutically acceptablesolvate form of a compound of the present invention that retains thebiological effectiveness of such compound. Examples of solvates include,but are not limited to, compounds of the invention in combination withwater, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethylacetate, acetic acid, ethanolamine, or mixtures thereof. It isspecifically contemplated that in the present invention one solventmolecule can be associated with one molecule of the compounds of thepresent invention, such as a hydrate. Furthermore, it is specificallycontemplated that in the present invention, more than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a dihydrate. Additionally, it is specificallycontemplated that in the present invention less than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a hemihydrate. Furthermore, solvates of thepresent invention are contemplated as solvates of compounds of thepresent invention that retain the biological effectiveness of thenon-hydrate form of the compounds.

The term “pharmaceutically acceptable salt,” as used herein, means asalt of a compound of the present invention that retains the biologicaleffectiveness of the free acids and bases of the specified derivativeand that is not biologically or otherwise undesirable.

The term “pharmaceutically acceptable formulation,” as used herein,means a combination of a compound of the invention, or apharmaceutically acceptable salt or solvate thereof, and a carrier,diluent, and/or excipients that are compatible with a compound of thepresent invention, and is not deleterious to the recipient thereof.Pharmaceutical formulations can be prepared by procedures known to thoseof ordinary skill in the art. For example, the compounds of the presentinvention can be formulated with common excipients, diluents, orcarriers, and formed into tablets, capsules, and the like. Examples ofexcipients, diluents, and carriers that are suitable for suchformulations include the following: fillers and extenders such asstarch, sugars, mannitol, and silicic derivatives; binding agents suchas carboxymethyl cellulose and other cellulose derivatives, alginates,gelatin, and polyvinyl pyrrolidone; moisturizing agents such asglycerol; disintegrating agents such as povidone, sodium starchglycolate, sodium carboxymethylcellulose, agar, calcium carbonate, andsodium bicarbonate; agents for retarding dissolution such as paraffin;resorption accelerators such as quaternary ammonium compounds; surfaceactive agents such as cetyl alcohol, glycerol monostearate; adsorptivecarriers such as kaolin and bentonite; and lubricants such as talc,calcium and magnesium stearate and solid polyethylene glycols. Finalpharmaceutical forms may be pills, tablets, powders, lozenges, saches,cachets, or sterile packaged powders, and the like, depending on thetype of excipient used. Additionally, it is specifically contemplatedthat pharmaceutically acceptable formulations of the present inventioncan contain more than one active ingredient. For example, suchformulations may contain more than one compound according to the presentinvention. Alternatively, such formulations may contain one or morecompounds of the present invention and one or more additional anti-HIVagents.

The term “inhibiting HIV replication” means inhibiting humanimmunodeficiency virus (HIV) replication in a cell. Such a cell may bepresent in vitro, or it may be present in vivo, such as in a mammal,such as a human. Such inhibition may be accomplished by administering acompound of the present invention, or a pharmaceutically acceptable saltor solvate thereof, to the cell, such as in a mammal, in anHIV-inhibiting amount. The quantification of inhibition of HIVreplication in a cell, such as in a mammal, can be measured usingmethods known to those of ordinary skill in the art. For example, anamount of a compound of the invention may be administered to a mammal,either alone or as part of a pharmaceutically acceptable formulation.Blood samples may then be withdrawn from the mammal and the amount ofHIV virus in the sample may be quantified using methods known to thoseof ordinary skill in the art. A reduction in the amount of HIV virus inthe sample compared to the amount found in the blood beforeadministration of a compound of the invention would represent inhibitionof the replication of HIV virus in the mammal. The administration of acompound of the invention to the cell, such as in a mammal, may be inthe form of single dose or a series of doses. In the case of more thanone dose, the doses may be administered in one day or they may beadministered over more than one day.

An “HIV-inhibiting agent” means a compound of the present invention or apharmaceutically acceptable salt or solvate thereof.

The term “anti-HIV agent,” as used herein, means a compound orcombination of compounds capable of inhibiting the replication of HIV ina cell, such as a cell in a mammal. Such compounds may inhibit thereplication of HIV through any mechanism known to those of ordinaryskill in the art.

The terms “human immunodeficiency virus-inhibiting amount” and“HIV-inhibiting amount,” as used herein, refer to the amount of acompound of the present invention, or a pharmaceutically acceptable saltor solvate thereof, required to inhibit replication of the humanimmunodeficiency virus (HIV) in vivo, such as in a mammal, or in vitro.The amount of such compounds required to cause such inhibition can bedetermined without undue experimentation using methods described hereinand those known to those of ordinary skill in the art.

The term “inhibiting HIV integrase enzyme activity,” as used herein,means decreasing the activity or functioning of the HIV integrase enzymeeither in vitro or in vivo, such as in a mammal, such as a human, bycontacting the enzyme with a compound of the present invention.

The term, “HIV integrase enzyme-inhibiting amount,” as used herein,refers to the amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, required todecrease the activity of the HIV integrase enzyme either in vivo, suchas in a mammal, or in vitro. Such inhibition may take place by thecompound of the present invention binding directly to the HIV integraseenzyme. In addition, the activity of the HIV integrase enzyme may bedecreased in the presence of a compound of the present invention whensuch direct binding between the enzyme and the compound does not takeplace. Furthermore, such inhibition may be competitive, non-competitive,or uncompetitive. Such inhibition may be determined using in vitro or invivo systems, or a combination of both, using methods known to those ofordinary skill in the art.

The term “therapeutically effective amount,” as used herein, means anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate thereof, that, when administered to a mammalin need of such treatment, is sufficient to effect treatment, as definedherein. Thus, a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvatethereof, is a quantity sufficient to modulate or inhibit the activity ofthe HIV integrase enzyme such that a disease condition that is mediatedby activity of the HIV integrase enzyme is reduced or alleviated.

The terms “treat”, “treating”, and “treatment” refer to any treatment ofan HIV integrase mediated disease or condition in a mammal, particularlya human, and include: (i) preventing the disease or condition fromoccurring in a subject which may be predisposed to the condition, suchthat the treatment constitutes prophylactic treatment for the pathologiccondition; (ii) modulating or inhibiting the disease or condition, i.e.,arresting its development; (iii) relieving the disease or condition,i.e., causing regression of the disease or condition; or (iv) relievingand/or alleviating the disease or condition or the symptoms resultingfrom the disease or condition, e.g., relieving an inflammatory responsewithout addressing the underlying disease or condition.

The terms “resistant,” “resistance,” and “resistant HIV,” as usedherein, refer to HIV virus demonstrating a reduction in sensitivity to aparticular drug. A mammal infected with HIV that is resistant to aparticular anti-HIV agent or combination of agents usually manifests anincrease in HIV viral load despite continued administration of the agentor agents. Resistance may be either genotypic, meaning that a mutationin the HIV genetic make-up has occurred, or phenotypic, meaning thatresistance is discovered by successfully growing laboratory cultures ofHIV virus in the presence of an anti-HIV agent or a combination of suchagents.

The terms “protease inhibitor” and “HIV protease inhibitor,” as usedherein, refer to compounds or combinations of compounds that interferewith the proper functioning of the HIV protease enzyme that isresponsible for cleaving long strands of viral protein into the separateproteins making up the viral core.

The terms “reverse transcriptase inhibitor” and “HIV reversetranscriptase inhibitor,” as used herein, refer to compounds orcombinations of compounds that interfere with the proper functioning ofthe HIV reverse transcriptase enzyme that is responsible for convertingsingle-stranded HIV viral RNA into HIV viral DNA.

The terms “fusion inhibitor” and “HIV fusion inhibitor,” as used herein,refer to compounds or combinations of compounds that bind to the gp41envelope protein on the surface of CD4 cells and thereby block thestructural changes necessary for the virus to fuse with the cell.

The terms “integrase inhibitor” and “HIV integrase inhibitor,” as usedherein, refer to a compound or combination of compounds that interferewith the proper functioning of the HIV integrase enzyme that isresponsible for inserting the genes of HIV into the DNA of a host cell.

The term “CCR5 antagonist,” as used herein, refer to compounds orcombinations of compounds that block the infection of certain cell typesby HIV through the perturbation of CCR5 co-receptor activity.

The terms “viral load” and “HIV viral load,” as used herein, mean theamount of HIV in the circulating blood of a mammal, such as a human. Theamount of HIV virus in the blood of mammal can be determined bymeasuring the quantity of HIV RNA in the blood using methods known tothose of ordinary skill in the art.

The term, “compound of the present invention” refers to any of theabove-mentioned compounds, as well as those in the Examples that follow,and include those generically described or those described as species.The term also refers to pharmaceutically acceptable salts or solvates ofthese compounds.

DETAILED DESCRIPTION

The compounds of the present invention are useful for modulating orinhibiting HIV integrase enzyme. More particularly, the compounds of thepresent invention are useful as modulators or inhibitors of HIVintegrase activity, and thus are useful for the prevention and/ortreatment of HIV mediated diseases or conditions (e.g., AIDS, and ARC),alone or in combination with other known antiviral agents.

In accordance with a convention used in the art, the symbol

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure. In accordance with another convention, in some structuralformulae herein the carbon atoms and their bound hydrogen atoms are notexplicitly depicted, e.g.,

represents a methyl group,

represents an ethyl group,

represents a cyclopentyl group, etc.

The compounds of the present invention may have asymmetric carbon atoms.The carbon-carbon bonds of the compounds of the present invention may bedepicted herein using a solid line

a solid wedge

or a dotted wedge

The use of a solid line to depict bonds to asymmetric carbon atoms ismeant to indicate that all possible stereoisomers at that carbon atomare included. The use of either a solid or dotted wedge to depict bondsto asymmetric carbon atoms is meant to indicate that only thestereoisomer shown is meant to be included. It is possible thatcompounds of the invention may contain more than one asymmetric carbonatom. In those compounds, the use of a solid line to depict bonds toasymmetric carbon atoms is meant to indicate that all possiblestereoisomers are meant to be included. The use of a solid line todepict bonds to one or more asymmetric carbon atoms in a compound of theinvention and the use of a solid or dotted wedge to depict bonds toother asymmetric carbon atoms in the same compound is meant to indicatethat a mixture of diastereomers is present. Unless otherwise stated, allpossible stereoisomers of the compounds of the present invention aremeant to be included herein.

The term “stereoisomers” refers to compounds that have identicalchemical constitution, but differ with regard to the arrangement oftheir atoms or groups in space. In particular, the term “enantiomers”refers to two stereoisomers of a compound that are non-superimposablemirror images of one another. The terms “racemic” or “racemic mixture,”as used herein, refer to a 1:1 mixture of enantiomers of a particularcompound. The term “diastereomers”, on the other hand, refers to therelationship between a pair of stereoisomers that comprise two or moreasymmetric centers and are not mirror images of one another.

If a derivative used in the method of the invention is a base, a desiredsalt may be prepared by any suitable method known to the art, includingtreatment of the free base with an inorganic acid, such as hydrochloricacid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; andthe like, or with an organic acid, such as acetic acid; maleic acid;succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid;oxalic acid; glycolic acid; salicylic acid; pyranosidyl acid, such asglucuronic acid or galacturonic acid; alpha-hydroxy acid, such as citricacid or tartaric acid; amino acid, such as aspartic acid or glutamicacid; aromatic acid, such as benzoic acid or cinnamic acid; sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid; and thelike.

If a derivative used in the method of the invention is an acid, adesired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary, or tertiary); an alkali metal oralkaline earth metal hydroxide; or the like. Illustrative Examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine; ammonia; primary, secondary, and tertiary amines;and cyclic amines, such as piperidine, morpholine, and piperazine; aswell as inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

A “solvate” is intended to mean a pharmaceutically acceptable solvateform of a specified compound that retains the biological effectivenessof such compound. Examples of solvates include, but are not limited to,compounds of the invention in combination with water, isopropanol,ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid,ethanolamine, or mixtures thereof.

A “pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of thespecified derivative, containing pharmacologically acceptable anions,and is not biologically or otherwise undesirable. Examples ofpharmaceutically acceptable salts include, but are not limited to,acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate),bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide,butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride,caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride,dihydrogenphosphate, edetate, edislyate, estolate, esylate,ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate,glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate,hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,y-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate,metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate,mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,phenylacetates, phenylbutyrate, phenylpropionate, phthalate,phospate/diphosphate, polygalacturonate, propanesulfonate, propionate,propiolate, pyrophosphate, pyrosulfate, salicylate, stearate,subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The compounds of the present invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention can beprepared by treating the base compound with a substantially equivalentamount of the selected mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or ethanol.Upon evaporation of the solvent, the desired solid salt is obtained. Thedesired acid salt can also be precipitated from a solution of the freebase in an organic solvent by adding an appropriate mineral or organicacid to the solution.

Those compounds of the present invention that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

In the case of agents that are solids, it is understood by those skilledin the art that the inventive compounds, agents and salts may exist indifferent crystal or polymorphic forms, all of which are intended to bewithin the scope of the present invention and specified formulas.

The compounds of the present invention may be formulated intopharmaceutical compositions as described below in any pharmaceuticalform recognizable to the skilled artisan as being suitable.Pharmaceutical compositions of the invention comprise a therapeuticallyeffective amount of at least one compound of the present invention andan inert, pharmaceutically acceptable carrier or diluent.

To treat or prevent diseases or conditions mediated by HIV, apharmaceutical composition of the invention is administered in asuitable formulation prepared by combining a therapeutically effectiveamount (i.e., an HIV Integrase modulating, regulating, or inhibitingamount effective to achieve therapeutic efficacy) of at least onecompound of the present invention (as an active ingredient) with one ormore pharmaceutically suitable carriers, which may be selected, forexample, from diluents, excipients and auxiliaries that facilitateprocessing of the active compounds into the final pharmaceuticalpreparations.

The pharmaceutical carriers employed may be either solid or liquid.Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar,pectin, acacia, magnesium stearate, stearic acid and the like. Exemplaryliquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the inventive compositions may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate or the like. Furtheradditives or excipients may be added to achieve the desired formulationproperties. For example, a bioavailability enhancer, such as Labrasol,Gelucire or the like, or formulator, such as CMC(carboxy-methylcellulose), PG (propyleneglycol), or PEG(polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle thatprotects active ingredients from light, moisture and oxidation, may beadded, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form, or formed into a trocheor lozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of syrup, emulsion, soft gelatin capsule,sterile injectable solution or suspension in an ampoule or vial ornon-aqueous liquid suspension. If a semi-solid carrier is used, thepreparation may be in the form of hard and soft gelatin capsuleformulations. The inventive compositions are prepared in unit-dosageform appropriate for the mode of administration, e.g., parenteral ororal administration.

To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of a compound of the present invention may be dissolvedin an aqueous solution of an organic or inorganic acid, such as 0.3 Msolution of succinic acid or citric acid. If a soluble salt form is notavailable, the agent may be dissolved in a suitable cosolvent orcombinations of cosolvents. Examples of suitable cosolvents includealcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,glycerin and the like in concentrations ranging from 0-60% of the totalvolume. In an exemplary embodiment, a compound of Formula I is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

Proper formulation is dependent upon the route of administrationselected. For injection, the agents of the compounds of the presentinvention may be formulated into aqueous solutions, preferably inphysiologically compatible buffers such as Hanks solution, Ringer'ssolution, or physiological saline buffer. For transmucosaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers known inthe art. Such carriers enable the compounds of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. Pharmaceutical preparations for oral use can be obtainedusing a solid excipient in admixture with the active ingredient (agent),optionally grinding the resulting mixture, and processing the mixture ofgranules after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include: fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; and cellulosepreparations, for example, maize starch, wheat starch, rice starch,potato starch, gelatin, gum, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol,and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

For administration intranasally or by inhalation, the compounds for useaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds of thepresent invention may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example, as an emulsionin an acceptable oil) or ion-exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds is a cosolvent systemcomprising benzyl alcohol, a nonpolar surfactant, a water-miscibleorganic polymer, and an aqueous phase. The cosolvent system may be a VPDco-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v ofthe nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol300, made up to volume in absolute ethanol. The VPD co-solvent system(VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution.This co-solvent system dissolves hydrophobic compounds well, and itselfproduces low toxicity upon systemic administration. The proportions of aco-solvent system may be suitably varied without destroying itssolubility and toxicity characteristics. Furthermore, the identity ofthe co-solvent components may be varied: for example, other low-toxicitynonpolar surfactants may be used instead of polysorbate 80; the fractionsize of polyethylene glycol may be varied; other biocompatible polymersmay replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and othersugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are known examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethylsulfoxide also may be employed, althoughusually at the cost of greater toxicity due to the toxic nature of DMSO.Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions also may comprise suitable solid- orgel-phase carriers or excipients. These carriers and excipients mayprovide marked improvement in the bioavailability of poorly solubledrugs. Examples of such carriers or excipients include calciumcarbonate, calcium phosphate, sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols. Furthermore,additives or excipients such as Gelucire®, Capryol®, Labrafil®,Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like maybe used. Further, the pharmaceutical composition may be incorporatedinto a skin patch for delivery of the drug directly onto the skin.

It will be appreciated that the actual dosages of the agents of thisinvention will vary according to the particular agent being used, theparticular composition formulated, the mode of administration, and theparticular site, host, and disease being treated. Those skilled in theart using conventional dosage-determination tests in view of theexperimental data for a given compound may ascertain optimal dosages fora given set of conditions. For oral administration, an exemplary dailydose generally employed will be from about 0.001 to about 1000 mg/kg ofbody weight, with courses of treatment repeated at appropriateintervals.

Furthermore, the pharmaceutically acceptable formulations of the presentinvention may contain a compound of the present invention, or apharmaceutically acceptable salt or solvae thereof, in an amount ofabout 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, orfrom about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg,or from about 10 mg to about 500 mg, or from about 25 mg to about 500mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg.

Additionally, the pharmaceutically acceptable formulations of thepresent invention may contain a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, in an amount fromabout 0.5 w/w % to about 95 w/w % , or from about 1 w/w % to about 95w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % toabout 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about10 w/w % to about 50 w/w %.

The compounds of the present invention, or a pharmaceutically acceptablesalt or solvate thereof, may be administered to a mammal suffering frominfection with HIV, such as a human, either alone or as part of apharmaceutically acceptable formulation, once a day, twice a day, orthree times a day.

Those of ordinary skill in the art will understand that with respect tothe compounds of the present invention, the particular pharmaceuticalformulation, the dosage, and the number of doses given per day to amammal requiring such treatment, are all choices within the knowledge ofone of ordinary skill in the art and can be determined without undueexperimentation. For example, see “Guidelines for the Use ofAntiretroviral Agents in HIV-1 Infected Adults and Adolescents,” UnitedStates Department of Health and Human Services, available athttp://www.aidsinfo.nih.gov/guidelines/ as of Oct. 29, 2004.

The compounds of the present invention may be administered incombination with an additional agent or agents for the treatment of amammal, such as a human, that is suffering from an infection with theHIV virus, AIDS, AIDS-related complex (ARC), or any other disease orcondition which is related to infection with the HIV virus. The agentsthat may be used in combination with the compounds of the presentinvention include, but are not limited to, those useful as HIV proteaseinhibitors, HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, inhibitors of HIV integrase, CCR5inhibitors, HIV fusion inhibitors, compounds useful as immunomodulators,compounds that inhibit the HIV virus by an unknown mechanism, compoundsuseful for the treatment of herpes viruses, compounds useful asanti-infectives, and others as described below.

Compounds useful as HIV protease inhibitors that may be used incombination with the compounds of the present invention include, but arenot limited to, 141 W94 (amprenavir), CGP-73547, CGP-61755, DMP-450,nelfinavir, ritonavir, saquinavir (invirase), lopinavir, TMC-126,atazanavir, palinavir, GS-3333, KNI-413, KNI-272, LG-71350, CGP-61755,PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450,AG-1776, MK-944, VX-478, indinavir, tipranavir, TMC-114, DPC-681,DPC-684, fosamprenavir calcium (Lexiva), benzenesulfonamide derivativesdisclosed in WO 03053435, R-944, Ro-03-34649, VX-385, GS-224338,OPT-TL3, PL-100, SM-309515, AG-148, DG-35-VIII, DMP-850, GW-5950X,KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003,Vb-19038, A-77003, BMS-182193, BMS-186318, SM-309515, JE-2147, GS-9005.

Compounds useful as inhibitors of the HIV reverse transcriptase enzymethat may be used in combination with the compounds of the presentinvention include, but are not limited to, abacavir, FTC, GS-840,lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine,didanosine, stavudine, zidovudine, tenofovir, amdoxovir, SPD-754,SPD-756, racivir, reverset (DPC-817), MIV-210 (FLG), beta-L-Fd4C(ACH-126443), MIV-310 (alovudine, FLT), dOTC, DAPD, entecavir, GS-7340,emtricitabine, alovudine,

Compounds useful as non-nucleoside inhibitors of the HIV reversetranscriptase enzyme that may be used in combination with the compoundsof the present invention include, but are not limited to, efavirenz,HBY-097, nevirapine, TMC-120 (dapivirine), TMC-125, etravirine,delavirdine, DPC-083, DPC-961, TMC-120, capravirine, GW-678248,GW-695634, calanolide, and tricyclic pyrimidinone derivatives asdisclosed in WO 03062238.

Compounds useful as CCR5 inhibitors that may be used in combination withthe compounds of the present invention include, but are not limited to,TAK-779, SC-351125, SCH-D, UK-427857, PRO-140, and GW-873140 (Ono-4128,AK-602).

Compounds useful as inhibitors of HIV integrase enzyme that may be usedin combination with the compounds of the present invention include, butare not limited to, GW-810781, 1,5-naphthyridine-3-carboxamidederivatives disclosed in WO 03062204, compounds disclosed in WO03047564, compounds disclosed in WO 03049690,5-hydroxypyrimidine-4-carboxamide derivatives disclosed in WO 03035076,and L-000810810.

Fusion inhibitors for the treatment of HIV that may be used incombination with the compounds of the present invention include, but arenot limited to enfuvirtide (T-20), T-1249, AMD-3100, and fused tricycliccompounds disclosed in JP 2003171381.

Other compounds that are useful inhibitors of HIV that may be used incombination with the compounds of the present invention include, but arenot limited to, Soluble CD4, TNX-355, PRO-542, BMS-806, tenofovirdisoproxil fumarate, and compounds disclosed in JP 2003119137.

Compounds useful in the treatment or management of infection fromviruses other than HIV that may be used in combination with thecompounds of the present invention include, but are not limited to,acyclovir, fomivirsen, penciclovir, HPMPC, oxetanocin G, AL-721,cidofovir, cytomegalovirus immune globin, cytovene, fomivganciclovir,famciclovir, foscarnet sodium, Isis 2922, KNI-272, valacyclovir,virazole ribavirin, valganciclovir, ME-609, PCL-016

Compounds that act as immunomodulators and may be used in combinationwith the compounds of the present invention include, but are not limitedto, AD-439, AD-519, Alpha Interferon, AS-101, bropirimine, acemannan,CL246,738, EL10, FP-21399, gamma interferon, granulocyte macrophagecolony stimulating factor, IL-2, immune globulin intravenous, IMREG-1,IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon,methionine-enkephalin, MTP-PE, granulocyte colony stimulating sactor,remune, rCD4, recombinant soluble human CD4, interferon alfa-2,SK&F106528, soluble T4 yhymopentin, tumor necrosis factor (TNF),tucaresol, recombinant human interferon beta, and interferon alfa n-3.

Anti-infectives that may be used in combination with the compounds ofthe present invention include, but are not limited to, atovaquone,azithromycin, clarithromycin, trimethoprim, trovafloxacin,pyrimethamine, daunorubicin, clindamycin with primaquine, fluconazole,pastill, ornidyl, eflornithine pentamidine, rifabutin, spiramycin,intraconazole-R51211, trimetrexate, daunorubicin, recombinant humanerythropoietin, recombinant human growth hormone, megestrol acetate,testerone, and total enteral nutrition.

Antifungals that may be used in combination with the compounds of thepresent invention include, but are not limited to, anidulafungin, C31G,caspofungin, DB-289, fluconzaole, itraconazole, ketoconazole,micafungin, posaconazole, and voriconazole.

Other compounds that may be used in combination with the compounds ofthe present invention include, but are not limited to, acmannan,ansamycin, LM 427, AR177, BMS-232623, BMS-234475, CI-1012, curdlansulfate, dextran sulfate, STOCRINE EL10, hypericin, lobucavir, novapren,peptide T octabpeptide sequence, trisodium phosphonoformate, probucol,and RBC-CD4.

In addition, the compounds of the present invention may be used incombination with anti-proliferative agents for the treatment ofconditions such as Kaposi∝s sarcoma. Such agents include, but are notlimited to, inhibitors of metallo-matrix proteases, A-007, bevacizumab,BMS-275291, halofuginone, interleukin-12, rituximab, paclitaxel,porfimer sodium, rebimastat, and COL-3.

The particular choice of an additional agent or agents will depend on anumber of factors that include, but are not limited to, the condition ofthe mammal being treated, the particular condition or conditions beingtreated, the identity of the compound or compounds of the presentinvention and the additional agent or agents, and the identity of anyadditional compounds that are being used to treat the mammal. Theparticular choice of the compound or compounds of the invention and theadditional agent or agents is within the knowledge of one of ordinaryskill in the art and can be made without undue experimentation.

The compounds of the present invention may be administered incombination with any of the above additional agents for the treatment ofa mammal, such as a human, that is suffering from an infection with theHIV virus, AIDS, AIDS-related complex (ARC), or any other disease orcondition which is related to infection with the HIV virus. Such acombination may be administered to a mammal such that a compound orcompounds of the present invention are present in the same formulationas the additional agents described above. Alternatively, such acombination may be administered to a mammal suffering from infectionwith the HIV virus such that the compound or compounds of the presentinvention are present in a formulation that is separate from theformulation in which the additional agent is found. If the compound orcompounds of the present invention are administered separately from theadditional agent, such administration may take place concomitantly orsequentially with an appropriate period of time in between. The choiceof whether to include the compound or compounds of the present inventionin the same formulation as the additional agent or agents is within theknowledge of one of ordinary skill in the art.

Additionally, the compounds of the present invention may be administeredto a mammal, such as a human, in combination with an additional agentthat has the effect of increasing the exposure of the mammal to acompound of the invention. The term “exposure,” as used herein, refersto the concentration of a compound of the invention in the plasma of amammal as measured over a period of time. The exposure of a mammal to aparticular compound can be measured by administering a compound of theinvention to a mammal in an appropriate form, withdrawing plasma samplesat predetermined times, and measuring the amount of a compound of theinvention in the plasma using an appropriate analytical technique, suchas liquid chromatography or liquid chromatography/mass spectroscopy. Theamount of a compound of the invention present in the plasma at a certaintime is determined and the concentration and time data from all thesamples are plotted to afford a curve. The area under this curve iscalculated and affords the exposure of the mammal to the compound. Theterms “exposure,” “area under the curve,” and “area under theconcentration/time curve” are intended to have the same meaning and maybe used interchangeably throughout.

Among the agents that may be used to increase the exposure of a mammalto a compound of the present invention are those that can as inhibitorsof at least one isoform of the cytochrome P450 (CYP450) enzymes. Theisoforms of CYP450 that may be beneficially inhibited include, but arenot limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitableagents that may be used to inhibit CYP 3A4 include, but are not limitedto, ritonavir and delavirdine.

Such a combination may be administered to a mammal such that a compoundor compounds of the present invention are present in the sameformulation as the additional agents described above. Alternatively,such a combination may be administered such that the compound orcompounds of the present invention are present in a formulation that isseparate from the formulation in which the additional agent is found. Ifthe compound or compounds of the present invention are administeredseparately from the additional agent, such administration may take placeconcomitantly or sequentially with an appropriate period of time inbetween. The choice of whether to include the compound or compounds ofthe present invention in the same formulation as the additional agent oragents is within the knowledge of one of ordinary skill in the art.

Several different assay formats are available to measureintegrase-mediated integration of viral DNA into target (or host) DNAand thus, identify compounds that modulate (e.g., inhibit) integraseactivity. In general, for example, ligand-binding assays may be used todetermine interaction with an enzyme of interest. When binding is ofinterest, a labeled enzyme may be used, wherein the label is afluorescer, radioisotope, or the like, which registers a quantifiablechange upon binding to the enzyme. Alternatively, the skilled artisanmay employ an antibody for binding to the enzyme, wherein the antibodyis labeled allowing for amplification of the signal. Thus, binding maybe determined through direct measurement of ligand binding to an enzyme.In addition, binding may be determined by competitive displacement of aligand bound to an enzyme, wherein the ligand is labeled with adetectable label. When inhibitory activity is of interest, an intactorganism or cell may be studied, and the change in an organismic orcellular function in response to the binding of the inhibitory compoundmay be measured. Alternatively, cellular response can be determinedmicroscopically by monitoring viral induced syncytium-formation (HIV-1syncytium-formation assays), for example. Thus, there are various invitro and in vivo assays useful for measuring HIV integrase inhibitoryactivity. See, e.g., Lewin, S. R. et al., Journal of Virology 73(7):6099-6103 (July 1999); Hansen, M. S. et al., Nature Biotechnology 17(6):578-582 (June 1999); and Butler, S. L. et al., Nature Medicine 7(5):631-634 (May 2001.

Exemplary specific assay formats used to measure integrase-mediatedintegration include, but are not limited to, ELISA, DELFIA® (PerkinElmerLife Sciences Inc. (Boston, Mass.)) and ORIGEN® (IGEN International,Inc. (Gaithersburg, Md.)) technologies. In addition, gel-basedintegration (detecting integration by measuring product formation withSDS-PAGE) and scintillation proximity assay (SPA) disintegration assaysthat use a single unit of double stranded-DNA (ds-DNA) may be used tomonitor integrase activity.

In one embodiment of the invention, the preferred assay is an integrasestrand-transfer SPA (stINTSPA) which uses SPA to specifically measurethe strand-transfer mechanism of integrase in a homogenous assayscalable for miniaturization to allow high-throughput screening. Theassay focuses on strand transfer and not on DNA binding and/or 3′processing. This sensitive and reproducible assay is capable ofdistinguishing non-specific interactions from true enzymatic function byforming 3′ processed viral DNA/integrase complexes before the additionof target DNA. Such a formation creates a bias toward compoundmodulators (e.g., inhibitors) of strand-transfer and not towardcompounds that inhibit integrase 3′ processing or prevent theassociation of integrase with viral DNA. This bias renders the assaymore specific than known assays. In addition, the homogenous nature ofthe assay reduces the number of steps required to run the assay sincethe wash steps of a heterogenous assay are not required.

The integrase strand-transfer SPA format consists of 2 DNA componentsthat model viral DNA and target DNA. The model viral DNA (also known asdonor DNA) is biotinylated ds-DNA preprocessed at the 3′ end to providea CA nucleotide base overhang at the 5′ end of the duplex. The targetDNA (also known as host DNA) is a random nucleotide sequence of ds-DNAgenerally containing [³H]-thymidine nucleotides on both strands,preferably, at the 3′ ends, to enable detection of the integrasestrand-transfer reaction that occurs on both strands of target ds-DNA.

Integrase (created recombinantly or synthetically and preferably,purified) is pre-complexed to the viral DNA bound to a surface, such asfor example, streptavidin-coated SPA beads. Generally, the integrase ispre-complexed in a batch process by combining and incubating dilutedviral DNA with integrase and then removing unbound integrase. Thepreferred molar ratio of viral DNA:integrase is about 1:about 5. Theintegrase/viral DNA incubation is optional, however, the incubation doesprovide for an increased specificity index with an integrase/viral DNAincubation time of about 15 to about 30 minutes at room temperature orat about 37° C. The preferred incubation is at about room temperaturefor about 15 minutes.

The reaction is initiated by adding target DNA, in the absence orpresence of a potential integrase modulator compound, to theintegrase/viral DNA beads (for example) and allowed to run for about 20to about 50 minutes (depending on the type of assay container employed),at about room temperature or about 37° C., preferably, at about 37° C.The assay is terminated by adding stop buffer to the integrase reactionmixture. Components of the stop buffer, added sequentially or at onetime, function to terminate enzymatic activity, dissociate integrase/DNAcomplexes, separate non-integrated DNA strands (denaturation agent),and, optionally, float the SPA beads to the surface of the reactionmixture to be closer in range to the detectors of, for example, aplate-based scintillation counter, to measure the level of integratedviral DNA which is quantified as light emitted (radiolabeled signal)from the SPA beads. The inclusion of an additional component in the stopbuffer, such as for example CsCl or functionally equivalent compound, isoptionally, and preferably, used with a plate-based scintillationcounter, for example, with detectors positioned above the assay wells,such as for example a TopCount® counter (PerkinElmer Life Sciences Inc.(Boston, Mass.)). CsCl would not be employed when PMT readings are takenfrom the bottom of the plate, such as for example when a MicroBetaecounter (PerkinElmer Life Sciences Inc. (Boston, Mass.)) is used.

The specificity of the reaction can be determined from the ratio of thesignal generated from the target DNA reaction with the viralDNA/integrase compared to the signal generated from the di-deoxy viralDNA/integrase. High concentrations (e.g., ≧50 nM) of target DNA mayincrease the d/dd DNA ratio along with an increased concentration ofintegrase in the integrase/viral DNA sample.

The results can be used to evaluate the integrase modulatory, such asfor example inhibitory, activity of test compounds. For example, theskilled artisan may employ a high-throughput screening method to testcombinatorial compound libraries or synthetic compounds. The percentinhibition of the compound may be calculated using an equation such asfor example (1−((CPM sample−CPM min)/(CPM max−CPM min)))*100. The minvalue is the assay signal in the presence of a known modulator, such asfor example an inhibitor, at a concentration about 100-fold higher thanthe IC₅₀ for that compound. The min signal approximates the truebackground for the assay. The max value is the assay signal obtained forthe integrase-mediated activity in the absence of compound. In addition,the IC₅₀ values of synthetic and purified combinatorial compounds may bedetermined whereby compounds are prepared at about 10 or 100-fold higherconcentrations than desired for testing in assays, followed by dilutionof the compounds to generate an 8-point titration curve with ½-logdilution intervals, for example. The compound sample is then transferredto an assay well, for example. Further dilutions, such as for example, a10-fold dilution, are optional. The percentage inhibition for aninhibitory compound, for example, may then be determined as above withvalues applied to a nonlinear regression, sigmoidal dose responseequation (variable slope) using GraphPad Prism curve fitting software(GraphPad Software, Inc., San Diego, Calif.) or functionally equivalentsoftware.

The stINTSPA assay conditions are preferably optimized for ratios ofintegrase, viral DNA and target DNA to generate a large and specificassay signal. A specific assay signal is defined as a signaldistinguishing true strand-transfer catalytic events from complexformation of integrase and DNA that does not yield product. In otherintegrase assays, a large non-specific component (background) oftencontributes to the total assay signal unless the buffer conditions arerigorously optimized and counter-tested using a modified viral DNAoligonucleotide. The non-specific background is due to formation ofintegrase/viral DNA/target DNA complexes that are highly stableindependent of a productive strand-transfer mechanism.

The preferred stINTSPA distinguishes complex formation from productivestrand-transfer reactions by using a modified viral DNA oligonucleotidecontaining a di-deoxy nucleoside at the 3′ end as a control. Thismodified control DNA can be incorporated into integrase/viral DNA/targetDNA complexes, but cannot serve as a substrate for strand-transfer.Thus, a distinct window between productive and non-productivestrand-transfer reactions can be observed. Further, reactions withdi-deoxy viral DNA beads give an assay signal closely matched to thetrue background of the assay using the preferred optimization conditionsof the assay. The true background of the assay is defined as a reactionwith all assay components (viral DNA and [³H]-target DNA) in the absenceof integrase.

Assay buffers used in the integrase assay generally contain at least onereducing agent, such as for example 2-mercaptoethanol or DTT, whereinDTT as a fresh powder is preferred; at least one divalent cation, suchas for example Mg⁺⁺, Mn⁺⁺, or Zn⁺⁺, preferably, Mg⁺⁺; at least oneemulsifier/dispersing agent, such as for example octoxynol (also knownas IGEPAL-CA or NP-40) or CHAPS; NaCl or functionally equivalentcompound; DMSO or functionally equivalent compound; and at least onebuffer, such as for example MOPS. Key buffer characteristics are theabsence of PEG; inclusion of a high concentration of a detergent, suchas for example about 1 to about 5 mM CHAPS and/or about 0.02 to about0.15% IGEPAL-CA or functionally equivalent compound(s) at least capableof reducing non-specific sticking to the SPA beads and assay wells and,possibly, enhancing the specificity index; inclusion of a highconcentration of DMSO (about 1 to about 12%); and inclusion of modestlevels of NaCl L<50 mM) and MgCl₂ (about 3 to about 10 mM) orfunctionally equivalent compounds capable of reducing the dd-DNAbackground. The assay buffers may optionally contain a preservative,such as for example NaN₃, to reduce fungal and bacterial contaminantsduring storage.

The stop buffer preferably contains EDTA or functionally equivalentcompound capable of terminating enzymatic activity, a denaturation agentcomprising, for example, NaOH or guanidine hydrochloride, and,optionally, CsCl or functionally equivalent compound capable ofassisting in floating the SPA beads to the top of the assay containerfor scintillation detection at the top of the reservoir and, possibly,minimizing compound interference. An example of an integrasestrand-transfer SPA is set forth in Example 13.

Alternatively, the level of activity of the modulatory compounds may bedetermined in an antiviral assay, such as for example an assay thatquantitatively measures the production of viral antigens (e.g., HIV-1p24) or the activities of viral enzymes (e.g., HIV-1 reversetranscriptase) as indicators of virus replication, or that measuresviral replication by monitoring the expression of an exogenous reportergene introduced into the viral genome (HIV-1 reporter virus assays)(Chen, B. K. et al., J. Virol. 68(2): 654-660 (1994); Terwilliger, E. F.et al., PNAS 86.3857-3861 (1989)). A preferred method of measuringantiviral activity of a potential modulator compound employs an HIV-1cell protection assay, wherein virus replication is measured indirectlyby monitoring viral induced host-cell cytopathic effects using, forexample, dye reduction methods as set forth in Example 14.

In one embodiment, the compounds of the present invention include thosehaving an EC₅₀ value against HIV integrase of at least 10⁻⁵ M (or atleast 10 μM) when measured with an HIV cell protection assay. In anotherembodiment are compounds of the present invention with an EC₅₀ valueagainst HIV integrase of at least 1 μM when measured with an HIV cellprotection assay. In yet another embodiment, the compounds of thepresent invention have an EC₅₀ against HIV integrase of at least 0.1 μMwhen measured with an HIV cell protection assay.

The inventive agents may be prepared using the reaction routes andsynthesis schemes as described below, employing the techniques availablein the art using starting materials that are readily available. Thepreparation of certain embodiments of the present invention is describedin detail in the following examples, but those of ordinary skill in theart will recognize that the preparations described may be readilyadapted to prepare other embodiments of the present invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be performed by modifications apparent to those skilled inthe art, e.g., by appropriately protecting interfering groups, bychanging to other suitable reagents known in the art, or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving adaptability for preparing other compounds of the invention.

Methods of Preparation

Scheme 1 depicts a method for formation of N-hydroxy lactam 6-5. Radicalbromination of a methyl substituted indole 6-1 can be achieved byvarious reagents (Jerry March, Advanced Organic Chemistry, 5th edition,John Whiley & Sons, 2001, p. 911-914) the most common beingN-bromosuccinimide (NBS). It will be apparent to those skilled in thearts that successful execution of this reaction can depend highly on thesubstitution pattern of the precursor 6-1. Reaction of an alkylhalide6-2 (X. Doisy et al., Bioorg. Med. Chem. 1999, 7, 921-932) with benzylhydroxylamine in a presence of a base such as triethylamine can providecompound 6-3. Treatment with sodium ethoxide in ethanol can result inlactame formation and cleavage of the phenylsulfonyl protecting group.Alkylation of 6-4 with an alkylhalide in the presence of a base such assodium hydride in DMF similar to the methods described in scheme 2 canprovide N-benzyloxy lactame 6-5. The benzyl protecting group can beremoved using various methods (T. W. Greene, Protective groups inOrganic Chemistry, 3^(rd) edition, John Wiley & Sons, 1999, p. 76-86)such palladium catalysed hydrogenation. As is obvious to those skilledin the art, different protecting groups instead of the benzyl groupmight be used to form the final product 6-6.

Scheme 2 depicts the synthesis of a 4-substituted azaindole 12-12. Ethyl2-methyl-1H-pyrrole-3-carboxylate 12-1 (Wee, A. G. H.; Shu, A. Y. L.;Djerassi, C. J. Org. Chem. 1984, 49, 3327-3336) can be treated with anorgano halide in the presence of a base such as NaH to provide pyrrole12-3. Bromination using a bromine source such as NBS followed by radicalbromination after the addition of a radical initiator such as benzoylperoxide can give compound 12-4 which can react with a tosyl glycineester 12-5 (Ginzel K. D., Brungs, P.; Steckan, E. Tetrahedron, 1989, 45,1691-1701) to provide 12-6. Cyclization of 12-6 to 12-7 can be effectedupon treatment with a base such as lithium hexamethyl disilazide.Catalytic hydrogenolysis (with e.g. Pd/C) can provide ester 12-8.Treatment of 12-8 with an organo halide and a base such as NaH can give12-9. The hydroxy group in 12-8 can be converted to the triflate 12-10using trifluoromethanesulfonic anhydride and a base such as triethylamine. Triflate 12-10 can undergo palladium catalyzed couplings such asthe Stille coupling with tributylstannylethene 12-11 in the presence ofLiCl (J. K. Stille, Angew. Chem. 1986, 98, 504; Angew. Chem. Int. Ed.Engl. 1986, 25, 508; W. J. Scott, J. K. Stille, J. Am. Chem. Soc. 1986,108, 3033; C. Amatore, A. Jutand, and A. Suarez J. Am. Chem. Soc. 1993,115, 9531-9541) using a catalyst such Pd(PPh₃)₂Cl₂ (T. Sakamoto, C.Satoh, Y. Kondo, H. Yamanaka, Chem. Pharm. Bull. 1993, 41, 81-86), toprovide 12-12 which can be treated with hydroxylamine to form 12-13.

Alternatively, compound 12-10 may be allowed to react with n-butyl vinylether in the presence of a palladium catalyst, a base, a phosphine, andlithium chloride, in a solvent at a temperature of about 70° C., toprovide compound 12-14. Compound 12-14 can then be allowed to react witha base, such as lithium hydroxide, and in the presence of a solvent,such as methanol, at about 60° C., followed by reaction with acetic acidat a temperature of about 120° C. to provide compound 12-15.

As shown in Scheme 2a below, compound 12-15 can be furtherfunctionalized at the 3-position to provide, for example, graminederivatives (12-16), aldehyde derivatives (12-17), carboxylic acidderivatives (12-18), and sulfonyl chloride derivatives (12-19). Each ofcompounds 12-16, 12-17, 12-18, and 12-19 can then be furtherfunctionalized to provide additional intermediate compounds that can befurther converted to compounds of formula (I).

As shown in Scheme 2b, compound 12-15, or derivatives of 12-15 as shownin Scheme 2a, can then be allowed to react with hydroxylamine to affordcompounds of formula (I).

Scheme 3 depicts a route for preparation of a cyclic compound 13-7.Ester 13-1 can undergo cyclization to form pyranone 13-4 as described byT. Sakamoto, Y. Kondo, A. Yasuhara, H. Yamanaka, Tetrahedron 1991, 47,1877-1886. Catalytic hydrogenation using a catalyst such as Pd/C cangive lactone 13-3. Ring opening of the lactone with a base such assodium hydroxide can give acid 13-5 which can be coupled with a suitableprotected hydroxylamine (e.g. O-tetrahydropyranyl hydroxylamine 13-5)using a coupling reagent such as HATU to form 13-6. Mitsunobu reactionconditions (e.g. triphenylphosphine and diisopropyl azodicarboxylate)can effect cyclization of 13-6 to form 13-7 (for a review, see D. L.Hughes, Org. Prep. Proced. Int. 1996, 28, 127-164). Removal of thetetrahydropyranyl group to provide 13-8 is expected to occur underacidic conditions.

Compound 14-8 can be obtained according to Scheme 4. Palladium catalyzedreaction of triflate 14-1 with an alkyne such as 14-2 can give 14-3.Catalytic hydrogenation using a catalyst such as Pd/C can give thepropanol 14-4. Saponification of the ester 14-4 with a base such assodium hydroxide can give acid 14-5 which can be coupled with a suitableprotected hydroxylamine (e.g. O-tetrahydropyranyl hydroxylamine 14-6)using a coupling reagent such as HATU to form 13-7. Mitsunobu reactionconditions (e.g. triphenylphosphine and diisopropyl azodicarboxylate)can effect cyclization of 14-7 to form 14-8 (for a review, see D. L.Hughes, Org. Prep. Proced. Int. 1996, 28, 127-164). Removal of thetetrahydropyranyl group to provide 14-9 is expected to occur underacidic conditions.

A general method for formation of compound 15-5 and 15-6 is shown inScheme 5. Palladium catalyzed reaction of triflate 15-1 with an alkyne15-2 can give ester 15-3. On treatment of the ester with hydroxylamineand a base such as sodium hydroxide using the conditions described by D.W. Knight, Tetrahedron Lett. 2002, 43, 9187-9189 the formation of 15-5and/or 15-6 is expected.

EXAMPLES

The examples below are intended only to illustrate particularembodiments of the present invention and are not meant to limit thescope of the invention in any manner.

In the examples described below, unless otherwise indicated, alltemperatures in the following description are in degrees Celsius (° C.)and all parts and percentages are by weight, unless indicated otherwise.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company or LancasterSynthesis Ltd., and used without further purification, unless otherwiseindicated.

The reactions set forth below were performed under a positive pressureof nitrogen, argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents. Analytical thin-layerchromatography was performed on glass-backed silica gel 60° F. 254plates (Analtech (0.25 mm)) and eluted with the appropriate solventratios (v/v). The reactions were assayed by high-pressure liquidchromotagraphy (HPLC) or thin-layer chromatography (TLC) and terminatedas judged by the consumption of starting material. The TLC plates werevisualized by UV, phosphomolybdic acid stain, or iodine stain.

¹H-NMR spectra were recorded on a Bruker instrument operating at 300 MHzand ¹³CNMR spectra were recorded at 75 MHz. NMR spectra are obtained asDMSO-d₆ or CDCl₃ solutions (reported in ppm), using chloroform as thereference standard (7.25 ppm and 77.00 ppm) or DMSO-d₆ ((2.50 ppm and39.52 ppm)). Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used:s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doubletof doublets, dt=doublet of triplets. Coupling constants, when given, arereported in Hertz.

Infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrometer asneat oils, as KBr pellets, or as CDCl₃ solutions, and when reported arein wave numbers (cm⁻¹). The mass spectra were obtained using LC/MS orAPCl. All melting points are uncorrected.

All final products had greater than 95% purity (by HPLC at wavelengthsof 220 nm and 254 nm).

All elemental analyses for compounds herein, unless otherwise specified,provided values for C, H, and N analysis that were within 0.4% of thetheoretical value, and are reported as “C, H, N.”

In the following examples and preparations, “LDA” means lithiumdiisopropyl amide, “Et” means ethyl, “Ac” means acetyl, “Me” meansmethyl, “Ph” means phenyl, (PhO)₂POCl means chlorodiphenylphosphate,“HCl” means hydrochloric acid, “EtOAc” means ethyl acetate, “Na₂CO₃”means sodium carbonate, “NaOH” means sodium hydroxide, “NaCl” meanssodium chloride, “NEt₃” means triethylamine , “THF” meanstetrahydrofuran, “DIC” means diisopropylcarbodiimide, “HOBt” meanshydroxy benzotriazole, “H₂0” means water, “NaHCO₃” means sodium hydrogencarbonate, “K₂CO₃” means potassium carbonate, “MeOH” means methanol,“i-PrOAc” means isopropyl acetate, “MgSO₄” means magnesium sulfate,“DMSO” means dimethylsulfoxide, “AcCI” means acetyl chloride, “CH₂Cl₂”means methylene chloride, “MTBE” means methyl t-butyl ether, “DMF” meansdimethyl formamide, “SOCl₂” means thionyl chloride, “H₃PO₄” meansphosphoric acid, “CH₃SO₃H” means methanesulfonic acid, “Ac₂O” meansacetic anhydride, “CH₃CN” means acetonitrile, and “KOH” means potassiumhydroxide.

Example 13-(4-Fluorobenzyl)-7-hydroxy-3,7-dihydro-6*pyrrolo[2,3-c]-1,7-naphthyridin-6-one

Step 1: Ethyl 1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (106.26 g,0.694 mol) (prepared by the method of: Wee, A. G. H.; Shu, A. Y. L.;Djerassi, C. J. Org. Chem. 1984, 49, 3327-3336) in anhydrous DMF (1.0L), under nitrogen, was added sodium hydride (60% in oil, 30.5 g, 0.763mol, 1.1eq.) in 5 portions over 1 hour. When gas evolution ceased,4-fluorobenzyl bromide (131.13 g, 0.694 mol) in anhydrous DMF (0.2 L)was added via pressure equalized addition funnel over 45 minutes. Themixture was allowed to stir at room temperature for 16 hours after theaddition was complete, then was poured into water (1.4 L) in a 4 Lseparatory funnel. The mixture was extracted with diethyl ether (5×1.0L) and the combined organic phases were washed with brine (3.0 L) anddried (Na₂SO₄). Filtration, rinsing of the filter cake with diethylether (0.5 L) and concentration in vacuo (approx. 20 Torr) gave thecrude product and DMF. Residual DMF was removed on a cold finger traprotary evaporator at full pump vacuum in a 40° C. water bath to give thecrude benzylate pyrrole as an orange oil. The crude product was purifiedby chromatography on a column of silica gel (125mm OD, 1 kg 230-400mesh, packed with hexanes-EtOAc 95:5) eluted with hexanes:EtOAc (95:5,2.0 L) and hexanes:EtOAc (90:10, 8.0 L) while collecting 500 mLfractions, using the flash technique. Fractions 4-18 were combined toafford ethyl 1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate (172.3g, 95%) as a clear, pale yellow, viscous liquid. TLC (Merck,hexanes:EtOAc 85:15, UV—+, cerium molybdate—+): Rf=0.26; LCMS (EclipseXDB-C8, 0.8mL/min, gradient 80:20 to 5:95 H₂O (+0.1% HOAc):CH₃CN—5minutes, APCl, +mode): RT-3.711 min, m/e=262.1 (base), 263.2 (30);¹H-NMR (300 MHz, CDCl₃): δ=1.33 (t, J=7.06 Hz, 3H), 2.43 (s, 3H), 4.26(q, J =7.06 Hz, 2H), 5.00 (s, 2H), 6.52 ( d, J=3.20 Hz, 1H), 6.58 (d,J=3.20 Hz, 1 H), 6.92-7.04 (m, 4H).

Step 2: Ethyl4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate

To NBS (267.5 g, 1.503 mol, 3 eq.) in anhydrous CC₁₄ (0.5 L) in a 3 L,3N round bottom flask, equipped with an internal temperature monitoringprobe, addition funnel, and reflux condenser, was added ethyl1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate (130.9 g, 0.501mol) in anhydrous CCl₄ (0.5 L) over 15 minutes. The internal temperaturerose to 43° C. during the addition and a transient red color developed,which faded upon completion of the addition. The mixture was allowed tostir for 15 minutes, then benzoyl peroxide (1.21 g, 5 mmol, 0.01 eq.)was added and the mixture was heated to an internal temperature of 77°C. (reflux) and maintained at that temperature for 1.5 hours. At thistime point LCMS (APCl) indicated complete reaction. The mixture wascooled to room temperature, the precipitated solid was removed byfiltration, the filter cake was rinsed with CCl₄ (0.3 L), and thecombined filtrates were concentrated in vacuo to give the crudetribromide as a red-brown semi-solid. The crude material was treatedwith dichloromethane (50 mL) and hexanes (250 mL) to produce a tan solidand a red-brown liquid. The solid was isolated by filtration, was rinsedwith dichloromethane:hexanes (10:90, 0.5 L) and was dried in vacuo atroom temperature to furnish 170.03 g (69%) of ethyl4,5-dibromo-2-bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylateas a pale, tan solid. The filtrates were concentrated in vacuo to give amother liquor that was purified by chromatography on a column of silicagel (70 mm OD, 400 g 230-400 mesh, hexanes:EtOAc 90:10, 250 mLfractions) using the flash technique. Fractions 3-6 provided anadditional 29.57 g of ethyl4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylateas a pale, tan solid. Total: 199.6 g (81%). TLC (Merck, hexanes:EtOAc90:10, UV—+, cerium molybdate—+): Rf=0.33; LCMS (Eclipse XDB-C8,0.8mL/min, gradient 80:20 to 5:95 H₂O (+0.1% HOAc):CH₃CN—5 minutes,APCl, +mode): RT—4.109 min, m/e=416.0 (50), 417.9 (base), 419 (50),M-Br; ¹H-NMR (300 MHz, CDCl₃): δ=1.39 (t, J=7.16 Hz, 3H), 4.35 (q,J=7.16 Hz, 2H), 4.77 (s, 2H), 5.36 (s, 2H), 6.96-7.07 (m, 4H).

Step 3: Ethyl4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate

To a stirring solution of methyl N-[(4-methylphenyl)sulfonyl]glycinate(51.75 g, 0.213 mol, prepared by the method of: Ginzel, K. D.; Brungs,P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous DMF (0.5L) was added NaH (60% in oil, 8.59 g, 0.215 mol) in one portion. Themixture was allowed to stir for 30 minutes (warms and returns to roomtemperature) at which time a solution ethyl4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate(105.92 g, 0.213 mol) in anhydrous DMF (0.5 L) was added over 1 hour.The mixture was allowed to stir at room temperature for 16 hours, thenthe DMF was removed in vacuo (approx 2 Torr, 40° C. water bath) and theoily residue was dissolved in dichloromethane (0.75 L), the solution waswashed with saturated aq. NH₄Cl (0.5 L), brine (0.5 L), and dried(Na₂SO₄). Filtration and concentration in vacuo provided the crudealkylated material as a viscous reddish oil. The crude material washeated in the presence of MeOH (0.75 L) until the MeOH was boiling, thendichloromethane was added slowly until solution was achieved. The redsolution was cooled to room temperature (see off-white crystals) and thecrystallization was completed by cooling in a refrigerator (4° C.) for16 hours. The ivory solid was isolated by filtration, the solid wasrinsed with diethyl ether:hexanes (0.5 L, 10:90 v/v) and the solid wasdried in a vacuum oven (approx. 20 Torr, 50° C.) overnight to furnishethyl4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate (108.2 g, 77%) as a freeflowing, fine, ivory solid. TLC (Merck, hexanes:EtOAc 75:25, UV—+,cerium molybdate—+—purple): Rf=0.38; LCMS (Eclipse XDB-C8, 0.8 mL/min,gradient 80:20 to 5:95 H₂O (+0.1% HOAc):CH₃CN—5 minutes, ESI, +mode):RT—4.436 min, m/e=680.8 (55), 681.8 (18), 682.9 (base), 683.9 (30),684.8 (62), 686.8 (10)—M+Na; ¹H-NMR (300MHz, CDCl₃): δ=1.24 (t, J=7.16Hz, 3H), 2.14 (s, 3H), 3.49 (s, 3H), 3.89 (s, 2H), 4.19 (q, J=7.16 Hz,2H), 4.55 (s, 2H), 7.02 (d, J=2.45 Hz, 2H), 7.04 (s, 2H), 7.28 (d,J=8.19 Hz, 2H), 7.59 (d, J=8.19 Hz, 2H)

Step 4: Methyl 2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1pyrrolo[2,3-c]pyridine-5-carboxylate

To solid LiHMDS (61.27 g, 0.366 mol), in a 3 L, 3-neck round bottomflask equipped with a 0.5 L pressure equalized addition funnel and aninternal temperature probe, was added anhydrous THF (0.5 L). The mixturewas placed under nitrogen and immersed in a dry ice-i-PrOH bath. Thesolution was allowed to stir until the internal temperature reached −78°C. (1.25 h). To this stirring cold solution was added a solution ofethyl4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-methoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate (107.43 g, 0.163 mol) inanhydrous THF (0.5 L) at such a rate that the internal temperature doesnot exceed −70° C. (2 hours). During the course of the addition, ayellow color was first noticed giving way to an orange/yellow solution,which then produced a precipitate and an orange/yellow solution. Thereaction was allowed to stir for 30 minutes after the addition wascomplete, at which point LCMS (sample taken at 15 minutes afteraddition) indicated the reaction was complete. The mixture was rapidlypoured into a 6 L separatory funnel, which had been charged withsaturated aq. NH₄Cl (1.5 L) and dichloromethane-methanol (95:5, 2 L).The mixture was rapidly shaken to distribute the reaction mixture andquench the reaction. The organic phase was separated; the aq. layer wasextracted with dichloromethane-methanol (95:5 v/v, 1 L). The combinedorganic phases were filtered to remove a fine white precipitate and thendried (Na₂SO₄). Concentration in vacuo afforded the crude cyclizedmaterial as a yellow solid, which was triturated with EtOH (0.6 L) andthe resulting white solid was isolated by filtration, washed withanhydrous ethyl ether (50 mL), and dried in a vacuum oven (approx. 20Torr, 50° C., 16 hours) to give 40.51 g (54.4%) of methyl2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylateas a powdery white solid after drying in a vacuum oven. The filtrate wasconcentrated in vacuo and the residue was triturated with diethylether/hexanes (50:50 v/v, 0.25 L) to give 10.69 g (14.3%) of methyl2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylateas a powdery white solid after drying in a vacuum oven (approx. 20 Torr,50° C., 16 hours). The filtrate was again treated under the sameconditions (0.1 L, 50:50 v/v diethyl ether-hexanes) to give anadditional 2.39 g (3.2%) for a total yield of 53.59 g (72%). TLC (Merck,CH₂C₁₂: EtOAc 50:50, UV—+, cerium molybdate—+): Rf=0.57; LCMS (EclipseXDB-C8, 0.8mL/min, gradient 80:20 to 5:95 H₂O (+0.1% HOAc):CH₃CN—5minutes, ESI, +mode): RT—3.790 min, m/e=456.9 (55), 458.8 (base), 459.9(15)—M+, 480.9—M+Na.; ¹H-NMR (300 MHz, CDCl₃): δ=4.03 (s, 3H), 5.48 (s,2H), 6.96-7.04 (m, 2H), 7.05-7.12 (m, 2H), 8.28 (s, 1H), 11.60 (s, 1H).

Step 5: Methyl 1-(4-fluorobenzyl)-4-hydroxy-1pyrrolo[2,3-c]pyridine-5-carboxylate

To a 2.5 L Parr flask was added methyl2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(67.28 g, 0.147 mol), methanol (1.5 L) and triethyl amine (32.70 g,0.323 mol, 2.2 eq.). Into this mixture was bubbled nitrogen for 10minutes, then 10% Pd/C (15.6 g) was carefully added. The bottle wasplaced on a Parr apparatus; evacuated/purged with nitrogen (3×) andhydrogen was added to 40 psi. Shaking was commenced and after 5 minutesthe pressure had gone to zero and the bottle was re-pressurized to 40psi. This was repeated 2× at which point the pressure lowered to 35 psiand remained. TLC and LCMS then indicated the reaction was complete(total time ca. 1 hour). The palladium was removed by filtration througha pad of Celite, the filter cake was rinsed with dichloromethane (1.0 L)and the combined filtrates were concentrated in vacuo to give the crudeproduct plus amine salts. The mixture was taken into EtOAc (2 L) andwater (1.0 L), the organic phase was separated, the aqueous layer wasextracted with EtOAc (0.6 L), and the combined organic phases werewashed with brine (1.0 L) and dried (Na₂SO₄). Filtration andconcentration in vacuo gave a powdery white solid which was dried in avacuum oven (approx. 20 Torr, 50° C., 16 hours) to afford 43.13 g (98%)of methyl1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate asa free flowing, powdery white solid. TLC (Merck, CH₂Cl₂:EtOAc 50:50,UV—+, cerium molybdate—+): Rf=0.45 (fluorescent blue); LCMS (EclipseXDB-C8, 0.8 mL/min, gradient 80:20 to 5:95 v/v H₂O (+0.1% HOAc):CH₃CN—5minutes, APCl, +mode): RT—3.217 min, m/e=301.1 (base, M+H); ¹H-NMR (300MHz, CDCl₃): δ=4.02 (s, 3H), 5.36 (s, 2H), 6.83 (d, J=3.10 Hz, 1H),7.07-7.13 (m, 2H), 7.17 (d, J=3.10 Hz, 1H), 8.31 (s, 1H), 11.40 (s, 1H).

Step 6: Methyl1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a stirred solution of the methyl1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(20.0 g, 66.7 mmol) and triethylamine (46.5 mL, 333 mmol) indichloromethane (200 mL) at 0 ° C. was added trifluoromethanesulfonicanhydride (33.6 mL, 200 mmol) dropwisely and the reaction stirred at 0 °C. for 1 0 minutes. It was quenched with water and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered,concentrated, and purified by chromatography with ethyl acetate/hexanes(1/1) to provide the title compound as brown solid (25.28 g, 88% yield).¹H NMR (CDCl₃): δ; 8.73 (s, 1H), 7.39 (d, 1H), 7.18 (t, 2H), 7.05 (t,2H), 6.80 (d, 1H), 5.43 (s, 2H), 4.02 (s, 3H). LCMS (API-ES, M+H⁺):433.0. HPLC: 96% purity.

Step 7: Method 1: Methyl4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a stirred solution of methyl1-(4-fluorobenzyl)-4-[(trifluoroacetyl)oxy]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin (E [preparedaccording to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet.Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under anitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). Theresulting mixture was heated to 140° C. for 2 hours. It was quenchedwith water, and extracted with ethyl acetate three times. The combinedorganic extracts were washed with water (2×30 mL), dried over sodiumsulfate, concentrated in vacuo and purified by Biotage flashchromatography. Elution with hexane:ethyl acetate (1:1) provided thetitle compound as brown glue (0.40 g, 35% yield). ¹H NMR (MeOD) δ; 8.50(s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J =6.8 Hz), 7.05 (t, 2H,J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz),1.37 (t, 3H, J=7.1 Hz). LCMS (APCl, M+H⁺): 355.2.

Method 2: Methyl4-(2-ethoxyvinyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a solution of methyl1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(2 g, 4.62 mmol) in DMF (27 mL) was added lithium chloride (0.59 mg,13.88 mmol). Dry nitrogen was bubbled through the mixture for for 10min, and then dichlorobis(triphenylphosphine)palladium(II) (0.16 g, 0.23mmol) was added. The mixture was heated to 79° C., and a solution ofethoxyvinyl tributyltin (mixture of isomers: 1,2-E:1,2-Z:1,1=1:0:0.97:0.18) [prepared according to A. Leusik, H. A . Budding, J. W.Marsman, J. Organomet. Chem., 1967, 9, 285-294] (1.82 g, 5.08 mmol) inDMF (23 mL). The resulting mixture was stirred for 9 h at 70° C. undernitrogen atmosphere. It was quenched with saturated sodium chloride andfiltered to remove solid precipitate then concentrated. Purification byflash chromatography (Biotage) over silica gel (1:1 to 1:3, hexane/ethylacetate) afforded the title product as brown glue (1.46 g, 89.2 %yield). LCMS (APCl, M+H⁺): 355.2.

Step 8:4-[(E)-2-Ethoxyvinyl]-1-(4fluorobenzyl)-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide

To methyl4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(0.1 g, 0.28 mmol) in methanol (10 mL) were added hydroxylamine (1 mL,50% in water, 15.2 mmol) and sodium hydroxide (63.8 mg, 1.59 mmol). Themixture was stirred at room temperature for 2 h, and 4N hydrochloricacid (0.5 mL, 1.9 mmol) was added. The mixture was concentrated toprovide 100 mg of the title compound that was used without furtherpurification in the next step. ¹H NMR (DMSO-d₆) δ ppm 11.76 (d, 1H,J=1.9 Hz), 8.88 (d, 1H, J=1.9 Hz), 8.60 (s, 1H), 7.83 (d, 1H, J=3.0 Hz),7.31 (t, 2H, J=8.9 Hz), 7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz),6.82 (d, 1 H, J=3.0 Hz), 6.66 (d, 1 H, J=13.2 Hz), 5.54 (s, 2H), 3.96(q, 2H, J=7.0 Hz), 1.28 (t, 3H, J=7.0 Hz). LCMS (APCl, M+H⁺): 356.

Step 9:3-(4-Fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one

A solution of4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide(100 mg, 0.28 mmol) in methanol (10 mL) and hydrochloric acid (37 w %, 1mL) was refluxed for 16 hours. It was quenched with saturated sodiumbicarbonate solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulfate, concentrated and purified by pre-HPLC toprovide the title compound as white powder. ¹H NMR (DMSO-d₆) δ; 11.50(s, 1H), 9.04 (s, 1H), 7.88 (d, 1H, J=3.0 Hz), 7.84 (d, 1H, J=7.5 Hz),7.13-7.19 (m, 3H), 6.93 (d, 1H, J=7.5 Hz), 5.65 (s, 2H). MS (APCl,M+H⁺): 310.1. HRMS calcd for C₁₇H₁₃N₃O₂F₁ (M+H⁺) 310.0992, found310.0991. HPLC: 94.3% purity.

Alternative Method for Preparation of4-[(E)-2-Ethoxyvinyl]-1-(4-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamideStep 1: Ethyl4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-ethoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate

To a stirring solution of ethyl4,5-dibromo-2-(bromomethyl)-1-(4-fluorobenzyl)-1H-pyrrole-3-carboxylate(104.0 g, 0.209 mol) and ethyl N-[(4-methylphenyl)sulfonyl]glycinate(53.7 g, 0.209 mol, prepared by the method of: Ginzel, K. D.; Brungs,P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701) in anhydrous THF (1.5L) was added NaH (60% in mineral oil, 8.409, 0.210 mol) in several smallportions. The mixture was allowed to stir at room temperature for 16hours. It was quenched with aq. NH₄Cl solution, and extracted with ethylacetate. The organic layer was dried over Na₂SO₄, concentrated and theresidue was purified by column chromatography with ethyl acetate/hexane(1:4, v:v) to provide the title compound as glue-like material (1 24 g,88% yield).

¹H NMR (CDCl₃) δ ppm 7.61 (d, J=4.7 Hz, 2H), 7.30 (d, J=5.7 Hz, 2 H),7.04 (d, J=5.6 Hz, 4 H), 5.60 (s, 2H), 4.55 (s, 2H), 4.20 (q, J=7.1 Hz,2 H), 3.94 (q, J=7.2 Hz, 2 H), 3.89 (s, 2H), 2.42 (s, 2H), 1.25 (t,J=7.2Hz, 3 H), 1.14 (t, J=7.1 Hz, 3 H).

Step 2: Ethyl 2,3-dibromo-1-(4-fluorobenzyl)4-hydroxy-1pyrrolo[2,3-c]pyridine-5-carboxylate

To a stirring solution of ethyl4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-ethoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate(124.2 g, 184.3 mol) in anhydrous THF (1.0 L) was added LiHMDS (405 mL,1.0M in THF, 0.405 mol) at −78° C. over 1 h. The mixture was quenchedwith aq. NH₄Cl, extracted with ethyl acetate. The organic layer wasdried over Na₂SO₄, and concentrated. The residue was purified by columnchromatography with ethyl acetate/hexane(1l/, v:v) to ethylacetate/dichloromethane (9/1) to give the title product (52.0 g 60%yield). ¹H NMR (DMSO-d6) δ ppm. 11.50 (s, 1 H), 8.63 (s, 1H), 7.16 (d,J=7.2 Hz, 4H), 5.60 (s, 2H), 5.67 (s, 2H), 4.39 (q, J=7.1 Hz, 2H,), 1.33(t, J=7.2 Hz, 3H). LC/MS (API-ES, M+H⁺): 473.0.

Step 3: Ethyl 1-(4-fluorobenzyl)-4-hydroxy-1*pyrrolo[2,3-c]pyridine-5-carboxylate

A suspension of ethyl2,3-dibromo-1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(52.0 g, 0.110 mol) and 10% Pd/C (0.5 g) in ethanol (2.0 L) was shakenin a Parr shaker under hydrogen (39 psi) for 23 h. The catalyst wasremoved by filtration. On concentration of the filtrate, the productprecipitated out. It was collected by filtration and dried under vacuumto provide the title compound. (34 g, 98% yield) ¹H NMR (DMSO-d6) δ ppm.11.66 (s, 1H), 8.89 (s, 1H), 8.14 (d, J=3.0 Hz, 1H) 7.37 (d, J=5.7 Hz,2H), 7.19 (d, J=6.6 Hz, 2H), 7.11 (d, J=3.0 Hz, 1H), 5.71 (s, 2H), 4.45(q, J=7.1 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H). LC/MS (API-ES, M+H⁺): 315 1.

Step 4: Ethyl1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a stirred solution of the ethyl1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(20.0 g, 63.7 mmol) and triethylamine (44.4 mL, 318.5 mmol) indichloromethane (150 mL) at 0° C. was added trifluoromethanesulfonicanhydride (32.0 mL, 190.1 mmol) dropwise and the reaction stirred for 1h. It was quenched with water, extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, filtered, concentrated and purifiedby chromatography with ethyl acetate/hexane (1/1) to provide the titlecompound as brown solid (17.6 grams, 78% yield). ¹H NMR (DMSO-d₆): δ;8.10 (s, 1H), 8.08 (d, 1H), 7.41 (t, 2H), 7.18 (t, 2H), 6.74 (d, 1 H),5.64 (s, 2H), 4.34 (q, 2H), 1.31 (t, 3H). LC/MS (API-ES, M+H⁺): 44.70.

Step 5: Ethyl4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a stirred solution of ethyl1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(10.09, 22.4 mmol) and ethoxyvinyl tributyltin [prepared according to A.Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9,285-294] (9.7 9, 26.9 mmol, mixture of E -1,2: Z-1,2: 1:1,ratio=1:0.3:0.1) in DMF (30 mL) under a nitrogen atmosphere were addedtriethylamine (3.2 mL, 22.4 mmol) anddichlorobis(triphenylphosphine)palladium(II) (1.0 g, 1.4 mmol). Theresulting mixture was heated to 140° C. for 10 minutes. It was quenchedwith aq NaHCO₃ solution, and extracted with ethyl acetate. The organiclayer was washed with brine (2×), dried over sodium sulfate,concentrated in vacuo and purified by Biotage flash chromatography.Elution with hexane:ethyl acetate (3:2) provided the title compound as abrown glue (2.1 g) pure E-isomer together with 5.6 g of a mixture ofE-1,2 and Z-1,2 and 1,1 isomers). ¹H NMR (DMSO-d6) δ; 8.69 (s, 1H), 7.85(d, J=3.3 Hz, 1H), 7.33 (t, J=6.8 Hz, 2H), 7.13-7.20 (m, 3H), 6.86 (d,J=3.3 Hz, 1 H), 6.43 (d, J=13 Hz, 1H), 5.55 (s, 2H), 4.27(q, J=7.2 Hz, 2H), 3.98 (q, J=7.0 Hz, 2 H), 1.29 (t, J=7.1 Hz, 6 H). LCMS (APCl, M+H⁺):369.1.

Step 6:4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide

To ethyl4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(0.2 g, 0.54 mmol) in methanol (5 mL) were added hydroxylamine (1 mL,50% in water, 15.2 mmol) and sodium hydroxide (0.0763 g, 1.9 mmol). Themixture was stirred at room temperature for 5 h, neutralized with 4N aq.HCl solution (0.48 mL, 1.9 mmol), and extracted with ethyl acetate. Theorganic extract was concentrated and recrystallized from ethylacetate/ethyl ether/hexane to give the title compound (0.12 g, 62%yield). ¹H NMR (DMSO-d₆) δ; 11.76 (d, 1H, J=1.9 Hz), 8.88(d, 1 H, J=1.9Hz), 8.60 (s, 1 H), 7.83 (d, 1 H, J=3.0 Hz), 7.31 (t, 2H, J=8.9 Hz),7.22 (d, 1H, J=13.2 Hz), 7.05 (t, 2H, J=8.9 Hz), 6.82 (d, 1H, J=3.0 Hz),6.66 (d, 1H), J=13.2 Hz), 5.54 (s, 2H), 3.96 (q, 2H, J=7.0 Hz), 1.28 (t,3H, J=7.0 Hz). LCMS (APCl, M+H⁺): 356.1. Anal. (C₁₉H₁₈FN₃O₃) C, H, N.HPLC: 95% purity.

Example 23-(4-Fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6I4pyrrolo[2,3-c]-1,7-naphthyridin-6-one

Step 1: 7-(4Fluorobenzyl)pyrano[3,4b]pyrrolo[3,2-d]pyridin-4(7H)-one

Method 1: A solution of methyl4-[2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(pure E, Z or E/Z mixture can be used) ( 0.17 g, 0.48 mmol) in methanol(5 mL) and hydrochloric acid (37w %, 10 mL) was refluxed for 2 hours.The mixture was quenched with saturated aq. sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate, filtered, concentrated and purified by prep-HPLC to provide thetitle compound as white powder (20 mg, 14% yield). Method 2: A solutionof ethyl4-[2-ethoxyvinyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(pure E, Z or E/Z mixture can be used) (1.1 g, 2.98 mmol) in methanol (5mL), water (5 mL) and hydrochloric acid (37 w %, 5 mL) was refluxed for16 hours. The mixture was was quenched with saturated aq. sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasdried over sodium sulfate, filtered, concentrated and purified byBiotage chromatography to provide the title compound as white powder(0.3 g, 34% yield).

¹H NMR (MeOD) δ; 8.93 (s, 1H), 7.80 (d, J=3.2 Hz, 1 H), 7.84 (d, J=5.5Hz, 1 H), 7.28 (d, 1H, J=5.5 Hz, 1 H), 7.03-7.10 (m, 5H), 5.64 (s, 2H).MS (APCl, M+H⁺): 295.1.

Step 2:7-(4-Fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one

A solution of7-(4-fluorobenzyl)pyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(7H)-one (0.30 g,0.102 mmol) and Pd/C (5% Pd, 50 mg) in methanol (100 mL) was shaken in aParr shaker under hydrogen (20 psi) for 16 hours. The catalyst wasfiltered off, the filtrate was concentrated and dried in vacuum toprovided the title compound as a solid (0.28 g, 4% yield). that was usedwithout further purification in the next step ¹H NMR (MeOD) δ; 8.77 (s,1H), 7.76 (d, 1H, J=3.0 Hz), 7.28 (d, 2H, J=5.1 Hz), 7.07 (d, 2H, J=5.1Hz), 6.86 (d, 1H, J=3.0 Hz), 4.66 (d, 2H, J=6 Hz), 7,28 (d, 2H, J=6 Hz).MS (APCl, M+H⁺): 297.1.

Step 3:1-(4-Fluorobenzyl)-4-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylicacid

To7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one(0.11 g, 0.37 mmol) in methanol (10 mL) was added sodium hydroxide(0.066 g, 1.65 mmol) in water (2.0 mL). The reaction was heated to 60°C. for 3 hours. After cooling down, the reaction mixture was neutralizedwith 4N hydrochloric acid (0.42 mL, 1.65 mmol). It was concentrated anddried in vacuo to provide the crude title compound as a white powder(0.11 g, 94%). ¹H NMR (DMSO-d₆) δ; 8.93 (d, 1H, J=1.9 Hz), 8.06 (s, 1H),7.36 (m, 2H), 7.16 (t, 2H, J=6.6 Hz), 6.96 (s, 1H), 5.63 (s, 2H), 3.66(t, 2H, J=6.8 Hz), 3.44 (t, 2H, J=6.8 Hz). LCMS (APCl, M+H⁺): 315.1.

Step 4:1-(4-Fluorobenzyl)-4-(2-hydroxyethyl)-*(tetrahydro-2H-pyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide

To1-(4-fluorobenzyl)-4-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylicacid (0.11 g, 0.35 mmol) in DMF (10 mL) were added triethylamine (0.15ml, 1.05 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine2-(aminooxy)tetrahydro-2H-pyran (0.05 g, 0.43 mmol), andO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU; 0.16 g, 0.42 mmol). The mixture was stirredfor 16 hours at ambient temperature. It was quenched with water (30 mL),extracted with ethyl acetate (50 mL) and washed with brine (2×50 mL).The organic extracts was dried over sodium sulfate, concentrated invacuo and purified by Biotage chromatography using 5% methanol indichloromethane as eluent to provide the title compound as a crudepowder (0.16 g) that was used without further purification in the nextstep. LCMS (APCl, M+H⁺): 414.2.

Step 5:7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H)-one

To a stirred solution of1-(4-fluorobenzyl)-4-(2-hydroxyethyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide(0.16 g, 0.39 mmol) and triphenylphosphine (0.12 g, 0.46 mmol) in THF(10 mL), was added dropwise diisopropylazodicarboxylate (0.09 mL, 94 mg,0.46 mmol) in THF (1 mL) was added. The resulting mixture was stirred atroom temperature for 1 hour, and the solvent was evaporated.Purification by Biotage chromatography provided 0.12 g of a crudematerial that was used without further purification in the next step.LCMS (APCl, M+H⁺): 396.2.

Step 6:3-(4-Fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6Spyrrolo[2,3-c]-1,7-naphthyridin-6-one

A stirred solution of the7-(4-fluorobenzyl)-1,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(2H-one(0.12 g, 0.30 mmol) in acetic acid (4 mL), THF (2 mL) and water (1 mL)was heated to 45° C. for 16 h and 100° C. for another 1 h. Concentrationand purification by pre-HPLC provided the title compound as white powder( 0.023 g, 24% yield) . ¹H NMR (DMSO-d₆) δ; 9.87 (s, 1H), 8.84 (s, 1H),7.85 (d, 1H, J=3.0 Hz), 7.32-7.34 (m, 2H), 7.15 ( d, 2H, J=8.7 Hz), 6.72(d, 1H, J=3.0 Hz), 5.57 (s, 2H), 3.80 (d, 2H, J=7.0 Hz), 3.30 (d, 2H,J=7.0 Hz). LCMS (APCl, M+H⁺): 312.1. HRMS calcd for C₁₇H₁₅N₃O₂F₁ (M+H⁺)312.1148, found 312.1158. HPLC: 98.3% purity.

Example 33-(4-Fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one

Step 1: Ethyl1-(4-Fluorobenzyl)-4-(3-hydroxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a solution of ethyl1-(4-fluorobenzyl)-4-{([(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(1.50 g, 3.36 mmol) in DMF (4 mL) was added propargyloxytrimethylsilane(0.73 g, 5.72 mmol), lithium chloride (0.214 g, 5.1 mmol), copper iodide(0.028 g ml, 0.15 mmol), triethylamine (7 ml, 50.4 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.052 g, 0.074 mmol). Theresulting mixture was stirred for 20 min at 140° C. in a microwavereactor (Personal Chemistry). The solvent was evaporated and 10 mL ethylacetate was added. After stirring for 10 min, the mixture was filteredthrough Celite and the filtrate was concentrated. Purification by flashchromatography (Biotage) over silica gel (1:3, hexane/ethyl acetate)afforded the title product as yellow oil (0.46 g, 46% yield). ¹H NMR(400 MHz, CHLOROFORM-D) δ ppm 8.69 (s, 1 H) 7.36 (d, J=3.28 Hz, 1 H)7.06-7.14 (m, 2 H) 6.98-7.06 (m, 2 H) 6.84 (d, J=2.53 Hz, 1 H) 5.40 (s,2 H) 4.67 (s, 2 H), 4.8 (q, J=7.07 Hz, 2 H) 1.46 (t, J=7.20 Hz, 3 H).LC-MS (APCl, M+H⁺): 353.1. HPLC: 96% purity.

Step 2: Ethyl1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate

To a solution of ethyl1-(4-fluorobenzyl)-4-(3-hydroxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(0.46 g, 1.31 mmol) in MeOH (6 mL) was added palladium, (10 wt. % onactivated carbon, 15 mg, 0.014 mmol). The resulting mixture was shakenin a Parr apparatus for 4 h at room temperature under H₂ at 60 psi. Themixture was filtered and concentrated to afford the title product asyellow oil (0.41 g, 88% yield). LC-MS (APCl, M+H⁺): 357.2. HPLC: 96%purity.

Step 3:1-(4-Fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylicacid

To a solution of ethyl1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate(0.41 g, 1.15 mmol) in MeOH (6 mL) was added a solution of sodiumhydroxide (92mg, 2.30 mmol) in 1 mL of water. The resulting mixture wasstirred for 5 h at 60° C. The mixture was acidified to pH=6.5 by 1 N HCland concentrated to afford the title product as brown solid (358 mg, 95%yield). LC-MS (APCl, M+H⁺): 329.1. HPLC: 96% purity.

Step 4:1-(4-Fluorobenzyl)-4-(3-hydroxypropyl)-*(tetrahydro-2Spyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide

To a solution of1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylicacid (358 mg, 1.1 mmol) in DMF (8 mL) was added triethylamine (333 mg,3.3 mmol), HATU (627 mg, 1.65 mmol) andO-(tetrahydro-2H-pyran-2-yl)-hydroxylamine. The resulting mixture wasstirred for 2.5 h at room temperature. The mixture was concentrated.Purification by flash chromatography (Biotage) over silica gel (100%ethyl acetate) afforded the title product as brown oil (149mg, 32%yield). LC-MS (APCl, M+H⁺): 428.2. HPLC: 96% purity.

Step 5:3-(4-Fluorobenzyl)-7-(tetrahydro-2H-pyran-2-yloxy)-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one

To a solution of1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide(149 mg, 0.35 mmol) in THF (4 mL), was added PPh₃ (110 mg, 0.42 mmol)and DIAD (85 mg, 0.42 mmol). The resulting mixture was stirred for 1 hat room temperature. The mixture was concentrated. Purification by flashchromatography (Biotage) over silica gel (100% ethyl acetate) affordedthe title product as brown oil (18.5 mg, 13% yield). LC-MS (APCl, M+H⁺):410.1. HPLC: 96% purity.

Step 6:3-(4-fluorobenzyl)7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one

3-(4-fluorobenzyl)-7-(tetrahydro-2H-pyran-2-yloxy)-7,8,9,10tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one (18.53 mg,0.045 mmol) was dissolved in acetic acid, THF and Water (3.5 ml, 5:1:1).The-resulting mixture was stirred for 1 h at room temperature. Themixture was concentrated and purified by preparative HPLC to provide thetitle compound as a white powder (9.0 mg, 61% yield). 1H NMR (300 MHz,MeOH) □ ppm 8.57 (s, 1 H) 7.60 (d, J=3.20 Hz, 1 H) 7.11-7.20 (m, 2 H)6.90-6.99 (m, 2 H) 6.72 (d, J=3.01 Hz, 1 H) 5.44 (s, 2 H) 3.51 (t,J=6.50 Hz, 2 H) 3.03 (t, J=7.16 Hz, 2 H) 2.14-2.25 (m, 2 H). LC-MS(APCl, M+H⁺): 329.1. HPLC: 98% purity.

Examples 4-30 Step 1:9-[(dimethylamino)methyl]-7-(4-fluorobenzyl)pyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(7H)-one

To a solution of enol lactone (1.00 9, 3.401 mmol) stirred by anoverhead stirrer in acetonitrile (25 mL) was added Eschenmoser's salt(0.64 g, 6.803 mmol) and the mixture was heated at reflux for 2 h. Thesolution was cooled to room temperature and the solid product wasfiltered. Saturated sodium bicarbonate was added to the filtrate and themixture was extracted with dichloromethane (3×1000 mL). The combinedorganic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure to give the product as a pure whitesolid (1.0 g, 84%). 1HNMR (DMSO-d6) δ ppm: 9.10 (1H, s), 7.87 (1H, s),7.68 (1H, d), 7.36 (1H, d), 7.34 (2H, m), 7.16 (2H, m), 5.62 (2H, s),2.20 (6H, s). LCMS (ESI, M+1) 352.

General Procedure A1: To a solution of the appropriateN,N-dimethylaminomethyl tricycle (1.0 eq, 0.197 M in dichloromethane)was added ethyl chloroformate (1.0 eq). The mixture was stirred for 1 hand then the appropriate alcohol (4.0 eq, 1 mM in anhydrous DMF) wasadded followed by diisopropyl ethylamine (5.0 eq). The mixture wasplaced under nitrogen and was warmed to 40° C. in an oil bath. Afterstirring for 48 h, the volatiles were removed in vacuo (ca. 2 torr) togive an oil. The crude material was diluted with ethyl acetate andwashed with water and brine. The organic phase was separated, dried oversodium sulfate, and concentrated in vacuo. The residue was stirred inether, filtered, and dried under vacuum to afford the desired product.

General Procedure A2: To a solution of the appropriateN,N-dimethylaminomethyl aromatic enol lactone (1.0 eq) indichloromethane (6 mL/mmol enol lactone) were addeddiisopropylethylamine (0.0 eq for free base, 1.0 eq for Hl or HCl saltof N,N-dimethylaminomethyl aromatic enol lactone) and ethylchloroformate (1.0 eq) at room temperature. After stirring at roomtemperature for ten minutes, DMF (4mL/mmol enol lactone), diisopropylethylamine (1.0 eq) and the amine (1.0 eq) were added to the reactionsolution at room temperature. After stirring at room temperature for anadditional hour, saturated aqueous sodium bicarbonate solution was addedto the reaction mixture and it was extracted with dichloromethane (2×).The extracts were dried over sodium sulfate, the organic layer wasconcentrated under vacuum, and the product was optionally purified byreverse phase HPLC (acetonitrile:water, 0.1% acetic acid) to provide thedesired compound.

Step 2:7-(4-fluorobenzyl)-4-oxo-4,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridine-9-carbaldehyde

To a solution of enol lactone (2.0 g, 6.803 mmol) in DMF (20 mL) wasadded Eschenmoser's salt (2.5 g, 13.605 mmol) and the mixture was heatedin a microwave at 130 C for 2 h. More Eschenmoser's salt (2.5 g, 13.605mmol) was added and the mixture was heated again in the microwave at 130C for 2 h. The mixture was concentrated under reduced pressure and theresulting residue was suspended in acetone:water (1:1) and filtered togive a the aldehyde as a pure pale brown solid (1.41 g, 64%). 1NMR(DMSO-d6) δ 9.98 (1H, s), 9.26 (1H, s), 8.93 (1H, s), 8.12 (1H, d), 7.75(1H, d), 7.47 (2H, m), 7.21 (1H, m), 5.77 (2H, x). LC/MS (ESI, M+1) 323.

General Procedure A3: To a solution of the appropriate aldehyde (1.0 eq)in dichloromethane (0.2 M) was added the appropriate amine (1.0 eq).After stirring at room temperature for 2 h, sodium triacetoxyborohydride(3.0 eq) was added. The mixture was allowed to stir at room temperaturefor an additional 18-24 h, after which time the solvent was removedunder vacuum. The remaining residue was dissolved in DMSO and purifiedby reverse phase prep HPLC (acetonitrile:water, 0.1% acetic acid) toprovide the desired compounds.

Step 3:7-(4fluorobenzyl)oxo-4,7-dihydropyrano[3,4-b]pyrrolo[3,2-depyridine-9-sulfonylchloride

To a solution of the7-(4-fluorobenzyl)pyrano[3,4-b]pyrrolo[3,2-d]pyridin-4(7H)-one(1.0 eq)in chlorosulfonic acid (60 eq, 0.55 M) was added thionyl chloride(30eq). The mixture was stirred for 2 hrs at room temperature and thereaction was judged to be complete by HPLC-MS analysis. The mixture wasadded dropwise to ice water and the suspension was filtered to providethe sulfonyl chloride as a pure, white solid in 86% yield. 1 HNMR(MeOH-d4) δ 9.31 (1 H, s), 8.95 (1H, s), 7.79 (1H, d), 7.74 (1H, d),7.47 (2H, m), 7.15 (2H, m), 5.80 (2H, s). LC/MS (ESI, M+1) 393.

General Procedure A5: To a solution of the appropriate sulfonyl chloride(1.0 eq, 0.13 M in THF) and diisopropyl ethylamine (DIEA, 1.1 eq) wasadded the amine (1.0 eq). The mixture was stirred for 2 h at roomtemperature or until the reaction was judged to be complete by HPLC-MSanalysis. The volatiles were removed under vacuum and the crude materialwas diluted with dichloromethane and washed with saturated sodiumbicarbonate. The organic phase was separated, dried over sodium sulfate,and concentrated under vacuum. The crude material was purified byreverse phase HPLC (acetonitrile:water, 0.1% AcOH) to provide thedesired compound.

Step 4:7-(4-fluorobenzyl)-4-oxo-4,7-dihydropyrano[3,4-b]pyrrolo[3,2-d]pyridine-9-carboxylicacid

To a stirring solution of the aldehyde (1.30 g, 4.034 mmol) indioxane:water (3:1, 40 mL) was added sodium chlorite (0.547 g, 6.050mmol) followed by sulfamic acid (2.23 g, 22.99 mmol). The solution wasstirred for several hours until LC/MS showed the reaction to becomplete. The dioxane was mostly removed under reduced pressure and theresulting suspension in water was filtered and the filtrate was washedwith acetone to provide the acid as an off-white solid (1.20 g, 88%).1HNMR (DMSO-d6) δ 9.20 (1H, s), 8.69 (1H, s), 8.38 (1H, d), 7.71 (1H,d), 7.44 (1H, m), 7.18 (2H, m), 5.72 (2H, s). LC/MS (M+1) 339.

General Procedure A6: To a solution of the appropriate carboxylic acid(1.0 eq, 0.07 M in DMF) and 4-methylmorpholine (NMM, 3.2 eq) was added2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 1.2 eq). The mixture wasstirred at room temperature for 1 h and the appropriate amine (2.0 eq)was added. The resulting mixture was allowed to stir at room temperaturefor several hours until the reaction was judged to be complete byHPLC-MS analysis. The volatiles were removed under vacuum and the crudematerial was diluted with ethyl acetate and washed with saturated sodiumbicarbonate. The organic phase was separated, dried over sodium sulfate,and concentrated under vacuum. The crude material was purified byreverse phase HPLC (acetonitrile:water, 0.1% AcOH) to provide thedesired compounds.

General Procedure B1: A solution of the enol lactone (1.0 eq) in ethanol(27 mL/mmol enol lactone) and hydroxylamine (50w % in water, 0.68mL/mmol enol lactone) was refluxed for 3 h or until the LC/MS showedcomplete conversion to the desired N-hydroxypyridone. The resultingsolution was concentrated and purified by reverse phase HPLC(acetonitrile: water, 0.1% AcOH) to provide the desired compound. No.Structure Name Proc. ¹H NMR 4

1- [(dimethylamino)methyl]- 3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(DMSO-D6, 400 MHz) δ 9.01 (1H, s), 7.80 (1H, d), 7.77 (1H, s), 7.31 (2H,m), 7.17 (1H, d), 7.16 (2H, m), 5.61 (2H, s), 3.60 (2H, s), 2.19 (6H, s)5

1-{[3-(4-fluorobenzyl)-7- hydroxy-6-oxo-6,7- dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1- yl]methyl}-L-prolinamide A2, B1 (DMSO-d6, 400MHz) δ 11.5 (1H, bs), 8.97 (1H, s), 7.84 (1H, s), 7.78 (1H, d), 7.26(1H, d), 7.25 (2H, m), 7.13 (2H, m), 6.89 (1H, bs, NH), 6.77 (1H, bs,NH), 5.61 (2H, s), 3.95 (2H, s), 3.09 (2H, m),# 2.10 (1H, m), 1.73 (4H,m) 6

3-(4-fluorobenzyl)-7- hydroxy-1-[(3- oxopiperazin-1-yl)methyl]-3,7-dihydro- 6H-pyrrolo(2,3-c]-1,7- naphthyridin-6-one A2, B1(DMSO-d6, 400 MHz) δ 9.03 (1H, s), 7.82 (1H, s), 7.80 (1H, s), 7.75 (1H,s), 7.34 (2H, m), 7.16 (2H, m), 5.62 (2H, s), 3.79 (2H, s), 3.12 (2H,m), 2.96 (2H, s), 2.63 (2H, m) 7

3-(4-fluorobenzyl)-7- hydroxy-1-[(4- methylpiperazin-1-yl)methyl]-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(MeOH-d4, 400 MHZ) δ 8.93 (1H, s), 7.78 (1H, d), 7.68 (1H, s), 7.48 (2H,d), 7.26 (2H, m), 7.05 (2H, m), 5.59 (2H, s), 3.88 (2H, s), 2.50-3.00(8H, m), 2.56 (3H, s) 8

1[(4-ethylpiperazin-1- yl)methyl]-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (MeOH-d4,400 MHz) δ 8.94 (1H, s), 7.78 (1H, d), 7.70 (1H, s), 7.43 (2H, d), 7.27(2H, m), 7.06 (2H, m), 5.60 (2H, s), 3.93 (2H, s), 3.75-2.50 (8H, m),3.09 (2H, q), 1.29 (3H, t) 9

3-(4-fluorobenzyl)-7- hydroxy-1-[(2- methoxyethoxy)methyl]-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (DMSO-D6,300 MHz) d 9.10, (1H, s), 7.90 (1H, s), 7.88 (1H, d), 7.38 (2H, m), 7.22(2H, t), 7.02 (1H, d), 5.66 (2H, s), 4.78 (2H, s), 3.66 (2H, m), 3.52(2H, m), 3.38 (3H, s). 10

1-(3,4- dihydroisoquinolin- 2(1H)-ylmethyl)-3-(4-fluorobenzyl)-7-hydroxy- 3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (DMSO-D6, 300 MHz) δ11.44(1H, s), 9.03 (1H,s), 7.86(1 H, s), 7.75 (1H, d), 7.35 (2H, m), 7.20 (3H, m), 7.08 (3H,m), 6.99 (1H, m), 5.64 (2H, s), 3.90 (2H, s), 3.60 (2H, s), 2.79 (4H, m)11

3-(4-fluorobenzyl)-7- hydroxy-1-{[methyl(pentyl)amino]methyl}-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (MeOD-D4, 300 MHz) δ 8.93 (1H, s), 7.75(2H,m), 7.40 (1H, d), 7.27 (2H, m), 7.06 (2H, t), 5.62 (2H, s), 4.17 (2H,s), 2.75 (2H, m), 2.49 (3H, m), 1.62 (1H, m), 1.26 (4H, m), 0.82 (3H, t)12

1-{[3-(4-fluorobenzyl)-7- hydroxy-6-oxo-6,7- dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1- yl]methyl)-D-prolinamide A2, B1 (DMSO-D6, 300MHz) δ11.46 (1H, s), 8.96 (1H, s), 7.83 (1H, s), 7.79 (1H, d), 7.25 (3H,m), 7.13 (2H, d), 6.88 (1H, s), 6.67 (1H, s), 5.60 (2H, s), 3.95 (2H,s), 3.07 (2H, m), 2.49 (1H, m),# 2.15 (1H, m), 1.71 (3H, m) 13

3-(4-fluorobenzyl)-7- hydroxy-1-[(1-oxo-2,8- diazaspiro[4,5]dec-8-yl)methyl]-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(DMSO-D6, 300 MHz) δ 9.01 (1H, s), 7.82 (1H, d), 7.76 (1H, s), 7.51 (1H,s), 7.32 (2H, m), 7.26 (1H, d), 7.15 (2H, t), 5.61 (2H, s), 3.68 (2H,s), 3.13 (2H, t), 2.82# (2H, d), 2.03 (2H, d), 1.90 (2H, m), 1.63 (2H,t), 1.28 (2H, d) 14

1- {[cyclohexyl(ethyl)amino]methyl}-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (DMSO-D6,300 MHz) δ11.44(1H, s), 9.02 (1H, s), 7.79 (2H, m), 7.44 (1H, d), 7.29(2H, m), 7.14 (2H, t), 5.62 (2H, s), 3.90 (2H, s), 3.31 (1H, m), 2.53(2H, q),# 1.72 (3H, m), 1.52 (1H, m), 1.24 (2H, m), 1.04 (3H, m), 0.94(4H, m) 15

3-(4-fluorobenzyl)-7- hydroxy-1-{[4-(2-oxo-2- pyrrolidin-1-ylethyl)piperazin-1- yl]methyl}-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (DMSO-D6, 300 MHz) δ11.47 (1H, s), 9.01 (1H,s), 7.76 (2H, m), 7.75 (1H, d), 7.33 (2H, m), 7.15 (3H, m), 5.60 (2H,s), 3.90 (2H, s), 3.70 (2H, s), 3.43 (2H, t),# 3.24 (2H, t), 3.03 (2H,s), 2.40 (4H, s), 1.82 (2H, m), 1.73 (2H, m) 16

3-(4-fluorobenzyl)-7- hydroxy-1-{[methyl (2- pyridin-2-ylethyl)amino]methyl}- 3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (DMSO-D6, 300 MHz) δ11.41 (1H, s), 8.99 (1H,s), 8.33 (1H, d), 7.75 (1H, s), 7.65 (1H, d), 7.55 (1H, t), 7.30 (2H,t), 7.11 (5H, m), 5.60 (2H, s), 3.73 (2H, s),# 2.89 (2H, m), 2.80 (2H,m), 2.25 (3H, s) 17

(3R)-1-{[3-(4- fluorobenzyl)-7-hydroxy- 6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7- naphthyridin-1- yl]methyl}-N,N-dimethylpyrrolidine-3- carboxamide A2, B1 (DMSO-D6, 300 MHz) δ11.46 (1H,s), 9.00 (1H, s), 7.68 (3H, m), 7.34 (2H, m), 7.16 (2H, t), 5.59 (2H,s), 4.08 (1H,d), 3.69 (1H, d), 3.45 (1H, m), 2.88 (2H, m),# 2.82 (3H,s), 2.69 (3H, s), 2.10 (1H, m), 1.70 (3H, m) 18

3-(4-fluorobenzyl)-7- hydroxy-1-({4-hydroxy-4- [(2-oxopyrrolidin-1-yl)methyl]piperidin-1- yl}methyl)-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (DMSO-D6, 300 MHz) δ11.50(1H, s), 9.00(1H, s),7.78 (2H, m), 7.33 (2H, m), 7.25 (1H, d), 7.16 (2H, t), 5.60 (2H, s),4.39 (1H, s), 3.68 (2H, s), 3.48 (2H, t),# 3.12 (2H, s), 2.50 (6H, m),2.18 (2H, t), 1.87 (2H, m), 1.41 (4H, s) 19

3-(4-fluorobenzyl)-7- hydroxy-1-[(5-oxo-1,4- diazepan-1-yl)methyl]-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (DMSO-D6,300 MHz) δ11.46 (1H, s), 9.01 (1H, s), 7.78 (2H, m), 7.54 (1H, m), 7.32(3H, m), 7.16 (2H, t), 5.61 (2H, s), 3.80 (2H, s), 3.09 (2H, m), 2.55(4H, m), 2.41 (2H, m) 20

1-{[3-(4-fluorobenzyl)-7- hydroxy-6-oxo-6,7- dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1- yl]sulfonyl)-L- prolinamide A5, B1 (CD3OD, 400MHz) d 8.97 (1H, s), 8.40 (1H, s), 7.90 (1H, d), 7.77 (1H, d), 7.26 (2H,m), 7.01 (2H, m), 5.60 (2H, s), 4.08 (1H, m), 3.52 (1H, m), 3.32 (1H,m), 1.85 (3H, m), 1.61 (1H, m) 21

3-(4-fluorobenzyl)-7- hydroxy-N-{2-(1H-indol- 3-yl)ethyl]-6-oxo-6,7-dihydro-3H-pyrrolo[2,3- c]-1,7-naphthyridine-1- sulfonamide A5, B1(CD3OD, 400 MHz) d 8.71 (1H, s), 7.96 (1H, s), 7.55 (1H, d), 7.35 (1H,d), 7.19 (2H, m), 6.98 (4H, m), 6.80 (1H, m), 6.56 (2H, m), 5.37 (2H,s), 3.27 (2H, m), 2.72 (2H, m) 22

3-(4-fluorobenzyl)-7- hydroxy-1-[(3- oxopiperazin-1-yl)sulfonyl]-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A5,B1 (DMSO-D6, 400 MHz) d 9.11 (1H, s), 8.64 (1H, s), 7.91 (1H, d), 7.45(3H, m), 7.15 (2H, m), 5.72 (2H, s), 3.60 (2H, m), 3.34 (2H, m), 3.18(2H, m) 23

3-(4-fluorobenzyl)-7- hydroxy-N,N-dimethyl-6- oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1- naphthyridine-1- sulfonamide A5, B1 (CD3OD, 400 MHz) d8.99 (1H, s), 8.32 (1H, s), 7.80 (2H, m), 7.20 (2H, m), 7.05 (2H, m),5.67 (2H, s), 2.69 (6H, s) 24

3-(4-fluorobenzyl)-7- hydroxy-6-oxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3- c]-1,7-naphthyridine-1- sulfonamide A5, B1(CD3OD, 400 MHZ) d 8.95 (1H, s), 8.28 (1H, s), 7.74 (1H, d), 7.66 (1H,d), 7.25 (2H, m), 7.02 (2H, m), 5.63 (2H, s), 3.65 (2H, m) 25

N,3-bis(4-fluorobenzyl)- 7-hydroxy-6-axo-6,7- dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1- sulfonamide A5, B1 (CD3OD, 400 MHz) d 8.90 (1H,s), 8.15 (1H, s), 7.73 (1H, d), 7.69 (1H, d), 7.25 (2H, m), 7.05 (2H,m), 6.88 (2H, s), 4.07 (2H, s) 26

3-(4-fluorobenzyl)-7- hydroxy-1-(pyrrolidin-1- ylcarbonyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A6, B1 (CD3OD, 400 MHz) d 8.92(1H, s), 8.00 (1H, s), 7.69 (1H, d), 7.23 (2H, m), 7.14 (1H, d), 6.98(2H, m), 5.60 (2H, s), 3.64 (2H, m), 3.44 (2H, m), 1.95 (2H, m), 1.85(2H, m) 27

1-[(4-acetylpiperazin-1- yl)carbonyl]-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A6, B1 (CD3OD,400 MHz) d 8.94 (1H, s), 7.93 (1H, s), 7.71 (1H, d), 7.25 (2H, m), 6.98(3H, m), 5.60 (2H, s), 3.70 (2H, m), 3.54 (4H, m), 2.05 (2H, s) 28

3-(4-fluorobenzyl)-7- hydroxy-6-oxo-N-(2- pyrazin-2-ylethyl)-6,7-dihydro-3H-pyrrolo[2,3- c]-1,7-naphthyridine-1- carboxamide A6, B1CD3OD, 400 MHz) d 8.90 (1H, s), 8.52 (1H, s), 8.48 (1H, d), 8.38 (1H,d), 7.96 (1H, s), 7.67 (2H, d), 7.23 (2H, m), 6.98 (2H, m), 5.60 (2H,s), 3.76 (2H, m), 3.11 (2H, m) 29

3-(4-fluorobenzyl)-7- hydroxy-6-oxo-N- (pyridin-2-ylmethyl)-6,7-dihydro-3H-pyrrolo[2,3- c]-1,7-naphthyridine-1- carboxamide A6, B1(CD3OD, 400 MHz) d 8.92 (1H, s), 8.54 (1H, s), 8.39 (1H, d), 8.12 (1H,s), 7.84 (2H, d), 7.65 (1H, d), 7.36 (1H, m), 7.24 (2H, m), 6.98 (2H,m), 5.60 (2H, s), 4.58 (2H, s) 30

3-(4-fluorobenzyl)-7- hydroxy-6-oxo-N-(2,2,2- trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3- c]-1,7-naphthyridine-1- carboxamide A6, B1(CD3OD, 400 MHz) d 8.92 (1H, s), 8.12 (1H, s), 7.88 (1H, d), 7.67 (1H,d), 7.24 (2H, m), 6.98 (2H, m), 5.60 (2H, s), 4.05 (2H, m) 31

1-({[(2S)-2,3- dihydroxypropyl]oxy}methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo(2,3-c]-1,7- naphthyridin-6-one A1, B1(DMSO-D6, 300 MHz) δ9.07, (1H, s), 7.92 (1H, s), 7.86 (1H, d), 7.36 (2H,m), 7.23 (2H, t), 7.07 (1H, d), 5.66 (2H, s), 4.82 (2H, s), 4.70 (1H,br), 4.52 (1H, br), 3.70-3.20 (4H, m). 32

tert-butyl 4-({]3-(4- fluorobenzyl)-7- hydroxy-6-oxo-6,7- dihydro-3H-pyrrolo[2,3-c]-1,7- naphthyridin-1- yl]methoxy}methyl)piperidine-1-carboxylate A1, B1 (DMSO-D6, 300 MHz) δ9.08, (1H, s), 7.92(2H, d), 7.36 (2H, t), 7.27 (2H, t), 6.96 (1H, d), 5.66 (2H, s), 4.77(2H, s), 3.90 (2H, d), 3.36 (1H, m), 2.64 (3H, m),# 1.60 (3H, m), 1.36(9H, s), 1.02 (2H, m) 33

3-(4-fluorobenzyl)-7- hydroxy-1-[(2-pyridin- 2-ylethoxy)methyl]-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A1, B1 (CD3OD,300 MHz) δ 8.87 (1H, s), 8.16 (1H, d), 7.80-7.50 (2H, m), 7.44 (1H, d),7.44-6.80 (7H, m), 5.63 (2H, s), 4.92 (2H, s), 3.88 (2H, m), 3.00 (2H,m). 34

1-{[2- (cyclohexyloxy)ethoxy ]methyl}-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A1, B1(DMSO-D6, 300 MHz) δ9.07, (1H, s), 7.92 (1H, s), 7.84 (1H, d), 7.37 (2H,m), 7.23 (2H, t), 7.08 (1H, d), 5.66 (2H, s), 4.83 (2H, s), 3.70-3.30(4H, m), 3.23# (1H, m), 1.86-1.32 (5H, m), 1.30-1.00 (5H, m). 35

1-[({[(4R)-2,2- dimethyl-1,3- dioxolan-4- yl]methyl}amino)methyl]-3-(4-fluorobenzyl)- 7-hydroxy-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A1, B1 (DMSO-D6, 300 MHz) δ9.10, (1H, s), 7.92 (1H,s), 7.87 (1H, d), 7.38 (2H, m), 7.22 (2H, t), 6.98 (1H, d), 5.66 (2H,s), 4.84 (2H, s),# 4.22 (1H, m), 3.98 (1H, t), 3.56 (3H, t), 1.26 (6H,d). 36

3-(4-fluorobenzyl)-7- hydroxy-1-[(2- methoxyethoxy)methyl]-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A1, B1 (DMSO-D6,300 MHz) δ9.10, (1H, s), 7.90 (1H, s), 7.88 (1H, d), 7.38 (2H, m), 5.66(2H, s), 4.78 (2H, s), 3.66 (2H, m), 3.52 (2H, m), 3.38 (3H, s). 37

3-(4-fluorobenzyl)-7- hydroxy-1- [(tetrahydro-2H- pyran-4-yloxy)methyl]-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-oneA1, B1 (DMSO-D6, 300 MHz) δ9.08, (1H, s), 7.90 (2H, m), 7.36 (2H, m),7.23 (2H, m), 7.07 (1H, d), 5.68 (2H, s), 4.86 (2H, s), 3.86 (2H, m),3.68 (1H, m), 3.38 (2H, m),# 1.92 (2H, m,), 1.49 (2H, m). 38

3-(4-fluorobenzyl)-7- hydroxy-1-{[(1R)-1- phenylethoxy]methyl}-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A1, B1 (DMSO-D6,300 MHz) δ9.07, (1H, s), 8.85 (1H, br) 7.83 (2H, m), 7.50-7.27 (7H, m),7.20 (2H, t), 6.97 (1H, d) 5.66 (2H, s), 4.66 (3H, m), 1.42 (3H, d). 39

3-(4-fluorobenzyl)-7- hydroxy-1-({[1- (hydroxymethyl)cyclopentyl]amino)methyl)- 3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A3, B1 (300 MHz, MeOH) d ppm 8.75 (s, 1H) 7.65-7.78(m, 2H) 7.22 7.32 (m, 2H) 7.19 (d, 1H) 7.04 (t, 2H) 5.52 (s, 2H) 4.38(s, 2H) 3.77 (s, 2H) 1.82-1.98 (m, 6H) 1.72 (s, 2H) 40

3-(4-fluorobenzyl)-7- hydroxy-1- [(propylamino)methyl]- 3,7-dihydro-6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A3, B1 (300 MHz, DMSO-D6) d ppm9.02 (s, 1H) 7.70-7.83 (m, 2H) 7.33 (m, 2H) 7.09-7.22 (m, 3H) 5.60 (s,2H) 3.97 (m, 2H) 1.44 (m, 2H) 0.86 (t, 3H) 41

3-(4-fluorobenzyl)-7- hydroxy-1-{[(3-methylbenzyl)amino]methyl}-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one A3, B1 (300 MHz, MeOH) d ppm 8.78 (s, 1H) 7.55-7.69(m, 2H) 7.23 (s, 4H) 7.13 (s, 1 H) 7.02 (s, 3H) 6.86 (s, 1 H) 5.53 (s,2H) 4.21 (s, 2 H) 3.99 (s, 2H) 2.32 (s, 3 H) 42

3-(4-fluorobenzyl)-7- hydroxy-1-({[(5- methylpyrazin-2-yl)methyl]amino)methyl)- 3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A3, B1 (300 MHz, MeOH) d ppm 8.80 (s, 1H) 8.42-8.50(m, 1H) 8.39 (s, 1H) 7.78 (d, 1 H) 7.66 (s, 1H) 7.18-7.33 (m, 3H) 7.05(t, 2H) 5.57 (s, 2H) 4.21 (s, 2H) 4.03# (s, 2H) 2.36-2.51 (s, 3H) 43

3-(4-fluorobenzyl)-7- hydroxy-1-({[4-(trifluoromethyl)benzyl]amino}methyl)3,7- dihydro-6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A3, B1 (300 MHz, MeOH) d ppm 8.89(s, 1H) 7.69 (m, 2H) 7.59 (m, 4H) 7.15-7.30 (m, 3H) 6.95-7.09 (m, 2 H)5.57 (s, 2H) 4.17 (s, 2 H) 4.00 (s, 2H) 44

3-(4-fluorobenzyl)-7- hydroxy-1-{[(pyridin- 2- ylmethyl)amino]methyl}-yl}-3,7-dihydro-6H- pyrrolo-2,3-c]-1,7- naphthyridin-6-one A3, B1(CD3OD, 300 MHz) d 8.87 (1H, s), 8.16 (1H, d), 7.80-7.50 (2H, m), 7.44(1H, d), 7.44-6.80 (7H, m), 5.63 (2H, s), 4.92 (2H, s), 3.88 (2H, m),3.00 (2H, m). 45

3-(4-fluorobenzyl)-7- hydroxy-7,8,9,10- tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3- c]azepin-6(3H)-one (300 MHz, MeOH) d ppm 8.65 (s, 1H)7.68 (d, 1H) 7.19-7.29 (m, 2H) 6.97-7.08 (m, 2H) 6.81 (d, 1H) 5.53 (s,2H) 3.60 (t, 2H) 3.12 (t, 2H) 2.22-2.35 (m, 2H) 46

8-butyl-3-(4- fluorobenzyl)-7- hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one (300 MHz, MeOH) d ppm 8.85 (s,1H) 7.69 (s, 1H) 7.26 (dd, 2H) 7.00-7.11 (m, 3H) 6.90 (s, 1H) 5.61 (s,2H) 2.87-2.97 (t, 2H) 1.73-1.86 (m, 2H) 1.42-1.57 (m, 2H) 1.00 (t, 3H)47

3-(4-fluorobenzyl)-7- hydroxy-8-methyl- 3,7-dihydro-6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one (400 MHz, MeOD) d ppm 8.85 (s,1H) 7.69 (d, 1H) 7.26 (dd, 2H) 7.02-7.09 (m, 3H) 6.94 (s, 1H) 5.61 (s,2H) 2.56 (s, 3H) 48

3-(4-fluorobenzyl)-7- hydroxy-1-{[(2- hydroxyethyl)(propyl)amino]methyl}-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one(300 MHz, DMSO-D6) d ppm 9.03 (s, 1H) 7.77 (d, 2H) 7.30 (m, 3H) 7.15 (m,2H) 5.63 (s, 2H) 3.86 (m, 2H) 3.46 (m, 2H) 3.39 (s, 2H) 1.43 (m, 2H)0.74 (m, 3H) 49

3-(4-fluorobenzyl)-7- hydroxy-1-{[2- (hydroxymethyl)piperidin-1-yl]methyl}-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2,B1 (300 MHz, DMSO-D6) d ppm 9.02 (s, 1H) 7.76 (d, 2H) 7.47 (s, 1H)7.26-7.38 (m, 2H) 7.16 (m, 2H) 5.63 (s, 2H) 4.55 (m, 2H) 3.72 (s, 2H)3.59 (s, 2H) 2.71 (m, 2H) 1.64 (m, 2H)# 1.33 (m, 2H) 50

1-{[[2- (diethylamino)ethyl](ethyl)amino]methyl}-3- (4-fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(300 MHz, DMSO-D6) d ppm 9.06 (s, 1H) 7.74-7.86 (m, 2H) 7.29-7.38 (m,2H) 7.16 (m, 3H) 5.62 2H) 3.86 (s, 2H) 2.66 (s, J=6.78 Hz, 4H) 2.54-2.60(m, 8H) 2.43 (m, 2H)# 1.08 (t, 3H) 0.85 (t, 6H) 51

1-{[ethyl(4- methylbenzyl)amino]methyl}-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(300 MHz, DMSO-D6) d ppm 9.00 (s, 1H) 7.84 (s, 1 H) 7.72 (d, 1H) 7.31(dd, 2 H) 7.24 (d, 1H) 7.10-7.19 (m, 4H) 7.03-7.10 (m, 2 H) 5.61 (s, 2H)3.81 (s, 2 H) 3.53 (s, 2H) 3.38 (m, 2# H) 2.24 (s, 3H) 0.99 (t, 3 H) 52

1-{[4- (ethylsulfonyl)piperazin- 1-yl]methyl}-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(300 MHz, DMSO-D6) d ppm 9.03 (s, 1H) 7.75-7.85 (m, 2H) 7.26-7.37 (m,2H) 7.11-7.25 (m, 3 H) 5.62 (s, 2H) 3.79 (s, 2 H) 3.40 (m, 4H) 3.14 (m,4# H) 3.01 (q, 2H) 1.17 (t, 3 H) 53

3-(4-fluorobenzyl)-7- hydroxy-1-[(4- hydroxypiperidin-1- yl)methyl]-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (300 MHz,DMSO-D6) d ppm 9.01 (s, 1H) 7.70-7.84 (m, 2H) 7.22-7.36 (m, 3H) 7.16 (m,2H) 5.60 (s, 2H) 3.66 (s, 2H) 2.72 (m, 2H) 2.08 (m, 2H) 1.67 (m, 2H)1.36 (m, 2H) 54

1- {[benzyl(methyl)amino]methyl}-3-(4- fluorobenzyl)-7-hydroxy-3,7-dihydro- 6H-pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1(300 MHz, DMSO-D6) d ppm 9.01 (s, 1H) 7.70-7.85 (m, 2H) 7.26-7.35 (m,6H) 7.10-7.26 (m, 4 H) 5.61 (s, 2 H) 3.77 (s, 2 H) 3.55 (s, 2 H) 2.07(s, 3 H) 55

3-(4-fluorobenzyl)-7- hydroxy-1-{[(7R)-7- hydroxyhexahydropyrrolo[1,2-a]pyrazin- 2(1H)-yl]methyl}-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (300 MHz, DMSO-D6) d ppm 9.01 (s, 1H)7.71-7.83 (m, 2H) 7.23-7.36 (m, 3H) 7.16 (t, 2H) 5.60 (s, 2H) 3.72 (s,2H) 3.18-3.27 (m, 2H) 2.88 (m, 1H)# 2.78 (m, 2H) 2.22 (m, 2H) 2.11 (d,2H) 1.71 (m, 1H) 1.40-1.54 (m, 2H) 56

3-(4-fluorobenzyl)-7- hydroxy-1- {[(3aR,7aR)-3- oxooctahydro-5H-pyrrolo[3,4-c]pyridin- 5-yl]methyl}-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (300 MHz, DMSO-D6) d ppm 8.96 (s, 1H) 7.74 (s,1H) 7.54 (d, 1H) 7.48 (s, 1H) 7.23-7.38 (m, 3H) 7.12 (t, 2H) 5.55 (s,2H)# 3.93 (m, 1H) 3.76 (d, 1H) 3.46 (d, 1H) 3.21 (s, 2H) 2.61-2.70 (m,1H) 2.18-2.34 (m, 2H) 1.81 (m, 1H) 1.48-1.62 (m, 1H) 1.1 57

3-(4-fluorobenzyl)-7- hydroxy-1- (morpholin-4- ylmethyl)-3,7-dihydro-6H- pyrrolo[2,3-c]-1,7- naphthyridin-6-one A2, B1 (300 MHz,DMSO-D6) d ppm 9.02 (s, 1H) 7.71-7.84 (m, 2H) 7.22-7.35 (m, 3H) 7.16 (t,2H) 5.61 (s, 2H) 3.72 (s, 2H) 3.55 (m, 4H) 2.43 (m, 4H) 58

3-(4-fluorobenzyl)-7- hydroxy-1-{[4-(2- morpholin-4-ylethyl)piperazin-1- yl]methyl}-3,7- dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (300 MHz, DMSO-D6) d ppm 9.02 (s, 1H)7.78-7.80 (m, 2H) 7.30-7.35 (m, 2H) 7.10-7.25 (m, 3 H) 5.61 (s, 2H) 3.72(s, 2 H) 3.55 (m, 16H) 2.40-2.60 (m, 4H) 59

3-(4-fluorobenzyl)-7- hydroxy-1- ({methyl[(1-phenyl- 1H-pyrazol-4-yl)methyl]amino}methyl)- 3,7-dihydro-6H- pyrrolo[2,3-c]-1,7-naphthyridin-6-one A2, B1 (300 MHz, DMSO-D6) d ppm 9.01 (s, 1H) 8.42 (s,1 H) 7.73-7.86 (m, 4H) 7.69 (s, 1H) 7.48 (t, 2H) 7.24-7.35 (m, 3H)7.10-7.24 (m, 3H) 5.62 (s, 2H)# 3.74 (s, 2H) 3.58 (s, 2H) 2.14 (s, 3H)

Example 60 Integrase Strand-Transfer Scintillation Proximity Assay

Oligonucleotides: Oligonucleotide#1—5′-(biotin)CCCCTTTTAGTCAGTGTGGAAAATCTCTAGCA-3′ (SEQ ID NO: 1) andoligonucleotide #2—5′-ACTGCTAGAGATTTTCCACACTGACTAAAAG-3′ (SEQ ID NO: 2),were synthesized by TriLink BioTechnologies, Inc. (San Diego, Calif.).The annealed product represents preprocessed viral ds-DNA derived fromthe LTR U5 sequence of the viral genome. A ds-DNA control to test fornon-specific interactions was made using a 3′ di-deoxy derivative ofoligonucleotide #1 annealed to oligonucleotide #2. The CA overhang atthe 5′ end of the non-biotinylated strand of the ds-DNA was createdartificially by using a complimentary DNA oligonucleotide shortened by 2base pairs. This configuration eliminates the requisite 3′ processingstep of the integrase enzyme prior to the strand-transfer mechanism.

Host ds-DNA was prepared as an unlabeled and [³H]-thymidine labeledproduct from annealed oligonucleotide #3—5-AAAAAATGACCAAGGGCTAATTCACT-3′(SEQ ID NO: 3), and oligonucleotide #4—5′-AAAAMAGTGMTTAGCCCTTGGTCA-3′(SEQ ID NO: 4), both synthesized by TriLink BioTechnologies, Inc. (SanDiego, Calif.). The annealed product had overhanging 3′ ends ofpoly(dA). Host DNA was custom radiolabeled by PerkinElmer Life SciencesInc. (Boston, Mass.) using an enzymatic method with a 12/1 ratio of[methyl-³H]dTTP/cold ds-DNA to yield 5′-blunt end ds-DNA with a specificactivity of >900 Ci/mmol. The radiolabeled product was purified using aNENSORB cartridge and stored in stabilized aqueous solution(PerkinElmer). The final radiolabeled product had six [³H]-thymidinenucleotides at both 5′ ends of the host ds-DNA.

Reagents: Streptavidin-coated polyvinyltoluene (PVT) SPA beads werepurchased from Amersham Biosciences (Piscataway, N.J.). Cesium chloridewas purchased from Shelton Scientific, Inc. (Shelton, Conn.). White,polystyrene, flat-bottom, non-binding surface, 96-well plates werepurchased from Corning. All other buffer components were purchased fromSigma (St. Louis, Mo.) unless otherwise indicated.

Enzyme Construction: Full-length wild type HIV-1 integrase (SF1)sequence (amino acids 1-288) was constructed in a pET24a vector(Novagen, Madison, Wis.). The construct was confirmed through DNAsequencing.

Enzyme Purification: Full length wild-type HIV Integrase was expressedin E.coli BL21 (DE3) cells and induced with 1 mM isopropyl-1thio-β-D-galactopyranoside (IPTG) when cells reached an optical densitybetween 0.8-1.0 at 600 nm. Cells were lysed by microfluidation in 50 mMHEPES pH 7.0, 75 mM NaCl, 5 mM DTT, 1mM4-(2-Aminoethyl)benzenesulfonylfluoride HCl (AEBSF). Lysate was thencentrifuged 20 minutes at 11 k rpm in GSA rotor in Sorvall RC-5B at 4°C. Supernant was discarded and pellet resuspended in 50 mM HEPES pH 7.0,750 mM NaCl, 5 mM DTT, 1 mM AEBSF and homogenized in a 40 mL Douncehomogenizer for 20 minutes on ice. Homogenate was then centrifuged 20minutes at 11 k rpm in SS34 rotor in Sorvall RC-5B at 4° C. Supernantwas discarded and pellet resuspended in 50 mM HEPES pH 7.0, 750 mM NaCl,25 mM CHAPS, 5 mM DTT, 1 mM AEBSF. Preparation was then centrifuged 20minutes at 11 k rpm in SS34 rotor in Sorvall RC-5B at 4° C.

Supernant was then diluted 1:1 with 50 mM HEPES pH 7.0, 25 mM CHAPS, 1mM DTT, 1 mM AEBSF and loaded onto a Q-Sepharose column pre-equilibratedwith 50 mM HEPES, pH 7.0, 375 mM NaCl, 25 mM CHAPS, 1 mM DTT, 1 mMAEBSF. The flow through peak was collected and NaCl diluted to 0.1 Mwith 50 mM HEPES pH 7.0, 25 mM CHAPS, 1 mM DTT, 0.5 mM AEBSF and loadedonto a SP-Sepharose column pre-equilibrated with 50 mM HEPES pH 7.0, 100mM NaCl, 25 mM CHAPS, 1 mM DTT, 0.5 mM AEBSF. After washing the columnwith the equilibration buffer, a 100 to 400 mM NaCl gradient was run.The eluted integrase was concentrated and run on a S-300 gel diffusioncolumn using 50 mM HEPES pH 7.0, 500 mM NaCl, 25 mM CHAPS, 1 mM DTT, 0.5mM AEBSF. The peak from this column was concentrated to 0.76 mg/mL andstored at −70° C. and later used for strand transfer assays. All columnswere run in a 4° C. cold room.

Viral DNA Bead Preparation: Streptavidin-coated SPA beads were suspendedto 20 mg/mL in 25 mM 3-morpholinopropanesulfonic acid (MOPS) (pH 7.2)and 1.0% NaN₃. Biotinylated viral DNA was bound to the hydrated SPAbeads in a batch process by combining 25 pmoles of ds-DNA to 1 mg ofsuspended SPA beads (10 μL of 50 μM viral DNA to 1 mL of 20 mg/mL SPAbeads). The mixture was incubated at 22° C. for a minimum of 20 min.with occasional mixing followed by centrifugation at 2500 rpm for 10min. However, the centrifugation speed and time may vary depending uponthe particular centrifuge and conditions. The supernatant was removedand the beads suspended to 20 mg/mL in 25 mM MOPS (pH 7.2) and 1.0%NaN₃. The viral DNA beads were stable for several weeks when stored at4° C. Di-deoxy viral DNA was prepared in an identical manner to yieldcontrol di-deoxy viral DNA beads.

Preparation of lntegrase-DNA Complex: Assay buffer was made as a 10×stock of 250 mM MOPS (pH 7.2), 500 mM NaCl, 50 mM3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 0.5%(octylphenoxy)polyethoxyethanol (NP40) (IGEPAL-CA) and 0.05% NaN₃. ViralDNA beads were diluted to 2.67 mg/mL in 1× assay buffer plus 3 mM MgCl₂,1% DMSO, and 10 mM fresh DTT. Integrase (IN) was pre-complexed to viralDNA beads in a batch process (IN/viral DNA/bead complex) by combiningdiluted viral DNA beads with integrase at a concentration of 385 nMfollowed by a minimum incubation time of 20 min. at 22° C. with gentleagitation. The sample was kept at 22° C. until transferred to the assaywells.

Preparation of Host DNA: Host DNA was prepared to 200 nM as a mixture ofunlabeled and [³H]T-labeled host DNA diluted in 1× assay buffer plus 8.5mM MgCl₂ and 15 mM DTT. Concentrations used were 4 nM [³H]T-labeled hostDNA and 196 nM unlabeled host DNA. This ratio generates a SPA signal of2000-3000 CPM in the absence of modulators such as inhibitors.

Strand-transfer Scintillation Proximity Assay: The strand-transferreaction was carried out in 96-well microtiter plates, with a finalenzymatic reaction volume of 100 μL. Ten microliters of compounds ortest reagents diluted in 10% DMSO were added to the assay wells followedby the addition of 65 μL of the IN/viral-DNA/bead complex and mixed on aplate shaker. Then 25 μL of host DNA was added to the assay wells andmixed on a plate shaker. The strand-transfer reaction was initiated bytransferring the assay plates to 37° C. dry block heaters. An incubationtime of 50 min., which was shown to be within the linear range of theenzymatic reaction, was used. The final concentrations of integrase andhost DNA in the assay wells were 246 nM and 50 nM, respectively.

The integrase strand-transfer reaction was terminated by adding 70 μL ofstop buffer (150 mM EDTA, 90 mM NaOH, and 6 M CsCl) to the wells.Components of the stop buffer function to terminate enzymatic activity(EDTA), dissociate integrase/DNA complexes in addition to separatingnon-integrated DNA strands (NaOH), and float the SPA beads to thesurface of the wells to be in closer range to the PMT detectors of theTopCount® plate-based scintillation counter (PerkinElmer Life SciencesInc. (Boston, Mass.)). After the addition of stop buffer, the plateswere mixed on a plate shaker, sealed with transparent tape, and allowedto incubate a minimum of 60 min. at 22° C. The assay signal was measuredusing a TopCount® plate-based scintillation counter with settingsoptimal for [³H]-PVT SPA beads. The TopCount® program incorporated aquench standardization curve to normalize data for color absorption ofthe compounds. Data values for quench-corrected counts per minute (QCPM)were used to quantify integrase activity. Counting time was 2 min./well.

The di-deoxy viral DNA beads were used to optimize the integrasestrand-transfer reaction. The di-deoxy termination of the viral ds-DNAsequence prevented productive integration of viral DNA into the host DNAby integrase. Thus, the assay signal in the presence of di-deoxy viralDNA was a measure of non-specific interactions. Assay parameters wereoptimized to where reactions with di-deoxy viral DNA beads gave an assaysignal closely matched to the true background of the assay. The truebackground of the assay was defined as a reaction with all assaycomponents (viral DNA and [3H]-host DNA) in the absence of integrase.

Determination of Compound Activity: The percent inhibition of thecompound was calculated using the equation (1−((QCPM sample−QCPMmin)/(QCPM max−QCPM min)))*100. The min value is the assay signal in thepresence of a known inhibitor at a concentration 100-fold higher thanthe IC₅₀ for that compound. The min signal approximates the truebackground for the assay. The max value is the assay signal obtained forthe integrase-mediated activity in the absence of compound (i.e. withDMSO instead of compound in DMSO).

Compounds were prepared in 100% DMSO at 100-fold higher concentrationsthan desired for testing in assays (generally 5 mM), followed bydilution of the compounds in 100% DMSO to generate an 11-point titrationcurve with ½-log dilution intervals. The compound sample was furtherdiluted 10-fold with water and transferred to the assay wells. Thepercentage inhibition for an inhibitory compound was determined as abovewith values applied to a nonlinear regression, sigmoidal dose responseequation (variable slope) using GraphPad Prism curve fitting software(GraphPad Software, Inc., San Diego, Calif.). Concentration curves wereassayed in duplicate and then repeated in an independent experiment.

Example 61 HIV-1 Cell Protection Assay

The antiviral activities of potential modulator compounds (testcompounds) were determined in HIV-1 cell protection assays using the RFstrain of HIV-1, CEM-SS cells, and the XTT dye reduction method(Weislow, O. S. et al., J. Natl. Cancer Inst. 81: 577-586 (1989)).Subject cells were infected with HIV-1 RF virus at an moi of 0.025 to0.819 or mock infected with medium only and added at 2×10⁴ cells perwell into 96 well plates containing half-log dilutions of testcompounds. Six days later, 50 μl of XTT solution (1 mg/ml XTTtetrazolium and 0.02 nM phenazine methosulfate) were added to the wellsand the plates were reincubated for four hours. Viability, as determinedby the amount of XTT formazan produced, was quantifiedspectrophotometrically by absorbance at 450 nm.

Data from CPE assays were expressed as the percent of formazan producedin compound-treated cells compared to formazan produced in wells ofuninfected, compound-free cells. The fifty percent effectiveconcentration (EC₅₀) was calculated as the concentration of compoundthat affected an increase in the percentage of formazan production ininfected, compound-treated cells to 50% of that produced by uninfected,compound-free cells. The 50% cytotoxicity concentration (CC₅₀) wascalculated as the concentration of compound that decreased thepercentage of formazan produced in uninfected, compound-treated cells to50% of that produced in uninfected, compound-free cells. The therapeuticindex was calculated by dividing the cytotoxicity (CC₅₀) by theantiviral activity (EC₅₀).

Example 62 Antiviral Data

IC₅₀ EC₅₀ Example (nM) (nM) 1 20 0.4 2 30 0.6 3 17 29 4 8 7 5 18 38 6 712 7 17 8 8 14 11 9 15 0.53 10 40 0.41 11 6 3 12 13 4 13 8 13 14 13 8 155 39 16 6 7 17 9 31 18 11 67 19 5 15 20 9 390 21 46 480 22 6 45 23 10 424 5 22 25 35 160 26 9 5 27 13 19 28 12 24 29 12 35 30 13 13 31 9 32 1086 33 26 3 34 45 2 35 45 0.4 36 20 0.4 37 23 1 38 120 0.3 39 79 4 40 62 241 42 3 42 54 3 43 122 0.8 44 31 0.74 45 24 20 46 49 9.6 47 11 0.23 4811 1.2 49 13 14 50 11.5 8.6 51 17.5 1.3 52 10.5 1.6 53 7 13 54 13.5 0.4255 7 69 56 11.5 14 57 7 0.32 58 22 32 59 19 0.74

1. A compound of formula (I)

wherein: R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl, wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups may be optionally substituted with at least one substituent independently selected from: halo, —OR²a , N(R^(12a)R^(12b)), C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)N(R^(12a)R^(12b)), —NR^(12a)C(O)R^(12a), —NR^(12a)C(NR^(12a))N(R^(12a)R^(12b)), —SR^(12a), —S(O)R^(12a), —S(O)₂R^(12a), —S(O)₂N(R^(12a)R^(12b)), C₁-C₈ alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl groups are optionally substituted with at least one substituent independently selected from halo, —C(R^(12a)R^(12b)R^(12c)), —OH, and C₁-C₈ alkoxy; R² is hydrogen or Cl-Co alkyl; R³ is hydrogen, C₁-C₈ alkyl, —(CR⁷R⁸)_(t)NR⁹R¹⁰, —S(O)_(z)NR⁹R¹⁰, —C(O)NR⁹R¹⁰, or C₁-C₈ heteroalkyl, wherein said C₁-C₈ heteroalkyl is optionally substituted with R¹¹; Z is —(CR⁴R⁴)_(n)—, —C(R⁴)═C(R⁴)—, —C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—, —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—, or —(CR⁴R⁴)_(n)—C(R⁴)═C(R⁴)—(CR⁴R⁴)_(n)—; each R⁴ is independently selected from hydrogen, halo, C₁-C₈ heteroalkyl, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₄ aryl, C₂-C₉ cycloheteroalkyl, and C₂-C₉ heteroaryl are optionally substituted with at least one R¹³; R⁵ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at least one C₃-C₈ cycloalkyl or C₆-C₁₄ aryl group; R⁶ is hydrogen; each R⁷ and R⁸, which may be the same or different, are independently selected from hydrogen and C₁-C₈ alkyl; R⁹ and R¹⁰, which may be the same or different, are independently selected from hydrogen, C₃-C₈ cycloalkyl, C₂-C₉ cycloheteroalkyl, and C₁-C₈ alkyl, wherein said C₁-C₈ alkyl may be optionally substituted by at least one C₂-C₉ cycloheteroalkyl, C₂-C₉ heteroaryl, halo, or C₆-C₁₄ aryl group, and wherein said C₆-C₁₄ aryl group may be optionally substituted by at least one C₁-C₈ alkyl or halo group; or R⁹ and R¹⁰, together with the nitrogen atom to which they are attached, form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹³ group; R¹¹ is C₃-C₈ cycloalkyl, C₁-C₈ heteroalkyl, C₂-C₉ cycloheteroalkyl, C₆-C₁₄ aryl, or C₂-C₉ heteroaryl, each of which is optionally substituted with at least one substituent independently selected from C₁-C₈ alkyl, C₆-C₁₄ aryl, C₂-C₉ heteroaryl, —CF₃, —COR^(12a), —CO₂R^(12a), and —OR^(12a); each R^(12a), R^(12b), and R^(12c), which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, and oxo; or R^(12a) and R^(12b), together with the nitrogen atom to which they are attached, may form a C₂-C₉ cycloheteroalkyl group; each R¹³ is independently selected from halo, C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷, —(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), —NR^(12a)R^(12b), and —CF₃; t is an integer from 1 to 3; each n, which may be the same or different, is independently selected and is an integer from 1 to4; and each z, which may be the same or different, is independently selected and is 0, 1, or 2; or a pharmaceutically acceptable salt or solvate thereof, with the proviso that R⁵ is not hydrogen when Z is —(CH₂)—, R¹ is 2,4-difluorobenzyl, and R², R³, and R⁶ are hydrogen.
 2. A compound according to claim 1, wherein R¹³ is selected from C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷, —(CR⁷R⁸)_(z)C(O)NR^(12a)R^(12b), and —NR^(12a)R^(12b).
 3. A compound according to claim 2, wherein R¹³ is selected from C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, C(O)R^(12a), —S(O)₂R⁷, —C(O)NR^(12a)R^(12b), and —NR^(12a)R^(12b).
 4. A compound according to claim 3, wherein R¹³ is selected from C₁-C₈ alkyl and —C(O)NR^(12a)R^(12b).
 5. A compound according to claim 1, wherein: R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ aryl group is optionally substituted with at least one substituent independently selected from halo, —C(R^(12a)R^(12b)R^(12c)), —OH, and C₁-C₈ alkoxy; R² is hydrogen; R³ is hydrogen, —CR⁷R⁸)_(t)NR⁹R¹⁰ or C₁-C₈ heteroalkyl, wherein said C₁-C₈ heteroalkyl is optionally substituted with R¹¹; R⁹ and R¹⁰, together with the nitrogen atom to which they are attached, form a C₂-C₉ cycloheteroalkyl group optionally substituted with at least one C₁-C₈ alkyl; each R^(12a), R^(12b), and R^(12c), which may be the same or different, is independently selected from hydrogen and C₁-C₈ alkyl; and each R¹³ is independently selected from halo, C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —NR^(12a)R^(12b), and —CF₃.
 6. A compound according to claim 1, wherein R¹ is C₁-C₈ alkyl substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ aryl group is optionally substituted with at least one halo.
 7. A compound according to claim 6, wherein R³ is hydrogen.
 8. A compound according to claim 6, wherein R³ is —(CR⁷R⁸)_(t)NR⁹R¹⁰.
 9. A compound according to claim 8, wherein R⁹ and R¹⁰, together with the nitrogen atom to which they are attached, form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹³ group.
 10. A compound according to claim 9, wherein R¹³ is selected from C₁-C₈ alkyl, —(CR⁷R⁸)_(t)OR⁷, —C(O)R^(12a), —S(O)₂R⁷, —C(O)NR^(12a)R^(12b), and —NR^(12a)R^(12b).
 11. A compound according to claim 10, wherein R¹³ is selected from C₁-C₈ alkyl and —(O)NR^(12a)R^(12b).
 12. A compound according to claim 6, wherein R³ is C₁-C₈ heteroalkyl optionally substituted with R¹¹.
 13. A compound according to claim 1, wherein Z is —C(H)═C(H)—.
 14. A compound according to claim 13, wherein R³ is —(CR⁷R⁸)_(t)NR⁹R¹⁰.
 15. A compound according to claim 14, wherein R⁹ and R¹⁰, together with the nitrogen atom to which they are attached, form a C₂-C₉ cycloheteroalkyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹³ group.
 16. A compound according to claim 15, wherein R¹³ is selected from C₁-C₈ alkyl and —C(O)NR^(12a)R^(12b).
 17. A compound according to claim 1, selected from 3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-3,7,8,9-tetrahydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3m-one; 1-[(dimethylamino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-L-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(4-methylpiperazin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-(3,4-dihydroisoquinolin-2(1H)-ylmethyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(pentyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-D-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(1-oxo-2,8-diazaspiro[4.5]dec-8-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-([cyclohexyl(ethyl)amino]methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[methyl(2-pyridin-2-ylethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; (3R)-1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methyl}-N,N-dimethylpyrrolidine-3-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-1-({4-hydroxy-4-[(2-oxopyrrolidin-1-yl)methyl]piperidin-1-yl}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(5-oxo-1,4-diazepan-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]sulfonyl}-L-prolinamide; 3-(4-fluorobenzyl)-7-hydroxy-N-[2-(1H-indol-3-yl)ethyl]-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzyl)-7-hydroxy-1-[(3-oxopiperazin-1-yl)sulfonyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-N,N-dimethyl-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzy)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; N,3-bis(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-sulfonamide; 3-(4-fluorobenzyl)-7-hydroxy-1-(pyrrolidin-1-ylcarbonyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-[(4-acetylpiperazin-1-yl)carbonyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2-pyrazin-2-ylethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(pyridin-2-ylmethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 3-(4-fluorobenzyl)-7-hydroxy-6-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridine-1-carboxamide; 1-[(4-ethylpiperazin-1-yl)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-({[(2S)-2,3-dihydroxypropyl]oxylmethyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; tert-butyl 4-({[3-(4-fluorobenzyl)-7-hydroxy-6-oxo-6,7-dihydro-3H-pyrrolo[2,3-c]-1,7-naphthyridin-1-yl]methoxy}methyl)piperidine-1-carboxylate; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-pyridin-2-ylethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[2-(cyclohexyloxy)ethoxy]methyl)-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-[({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}amino)methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(2-methoxyethoxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(tetrahydro-2H-pyran-4-yloxy)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(1R)-1-phenylethoxy]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(propylamino)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(3-methylbenzyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-({[(5-methylpyrazin-2-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-({[4-(trifluoromethyl)benzyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(3-(4-fluorobenzyl)-7-hydroxy-1-{[(pyridin-2-ylmethyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-7,8,9,10-tetrahydropyrrolo[3′,2′:4,5]pyrido[2,3-c]azepin-6(3H)-one; 8-butyl-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-8-methyl-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one, 3-(4-fluorobenzyl)-7-hydroxy-1-{[(2-hydroxyethyl)(propyl)amino]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[2-(hydroxymethyl)piperidin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[[2-(diethylamino)ethyl](ethyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[ethyl(4-methylbenzyl)amino]methyl}-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 1-{[4-(ethylsulfonyl)piperazin-1-yl]methyl]-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-[(4-hydroxypiperidin-1-yl)methyl]-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-napthyridin-6-one; 1-{[benzyl(methyl)amino]methyl-3-(4-fluorobenzyl)-7-hydroxy-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(7R)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{[(3aR ,7aR)-3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-(morpholin-4-ylmethyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; 3-(4-fluorobenzyl)-7-hydroxy-1-{([4-(2-morpholin-4-ylethyl)piperazin-1-yl]methyl}-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; and 3-(4-fluorobenzyl)-7-hydroxy-1-({methyl[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}methyl)-3,7-dihydro-6H-pyrrolo[2,3-c]-1,7-naphthyridin-6-one; or a pharmaceutically acceptable salt or solvate thereof.
 18. A pharmaceutical composition, comprising a therapeutically effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
 19. A method of inhibiting HIV integrase enzyme activity, comprising contacting said integrase enzyme with an HIV integrase-inhibiting amount of at least one compound according to claim
 1. 20. A method of treating HIV infection in an HIV-infected mammal, comprising administering to said mammal a therapeutically effective amount of at least one compound according to claim
 1. 